To see the other types of publications on this topic, follow the link: Receptor de calcitonina.
Journal articles on the topic 'Receptor de calcitonina'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Receptor de calcitonina.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Maciel, Rui M. B. "O Laboratório no Diagnóstico e Seguimento de Doenças Auto-Imunes e Neoplásicas de Tiróide." Arquivos Brasileiros de Endocrinologia & Metabologia 46, no. 1 (February 2002): 65–71. http://dx.doi.org/10.1590/s0004-27302002000100009.
Full textAbstract:
O laboratório é fundamental no diagnóstico das doenças auto-imunes e neoplásicas da tiróide. O teste mais importante para o diagnóstico etiológico da tiroidite de Hashimoto, doença de alta prevalência, é a determinação do anticorpo anti-tiroperoxidase (A-TPO), dosagem que pode também ser útil no diagnóstico de doença de Graves, do risco de hipotiroidismo em pacientes com hipotiroidismo sub-clínico e do risco de gestantes apresentarem tiroidite pós-parto. Outro teste útil nas doenças autoimunes é a determinação dos anticorpos anti-receptor de TSH (TRAb) naqueles casos de doença de Graves pouco sintomáticos ou quando a mesma ocorre em pacientes com bócio multi-nodular. Nas doenças neoplásicas da tiróide, a tiroglobulina (Tg) é fundamental e de alta sensibilidade no seguimento dos pacientes com câncer diferenciado da tiróide (papilífero e folicular), enquanto que a dosagem de calcitonina é obrigatória para o diagnóstico e seguimento do câncer medular da tiróide.
2
Blakely, P., D. A. Vaughn, and D. D. Fanestil. "Amylin, calcitonin gene-related peptide, and adrenomedullin: effects on thiazide receptor and calcium." American Journal of Physiology-Renal Physiology 272, no. 3 (March 1, 1997): F410—F415. http://dx.doi.org/10.1152/ajprenal.1997.272.3.f410.
Full textAbstract:
We previously reported that salmon calcitonin, but not rat calcitonin, increased renal thiazide receptor (TZR) density and decreased renal calcium [urinary calcium excretion (U(Caex))] in the rat. Since calcitonins, islet amyloid polypeptide (amylin), calcitonin-gene related peptide (CGRP), and adrenomedullin interact with a family of calcitonin-related receptors, we examined the effects of these peptides on 1) TZR density, as quantitated by binding of [3H]metolazone to renal membranes; 2) plasma ionic composition; and 3) urinary electrolyte excretion. Subcutaneous amylin both increased TZR density nearly twofold and decreased U(Caex), with maximal effects by 24 h. The decreased U(Caex) occurred with plasma amylin levels in the physiological range, whereas the increased TZR did not reach maximum even with plasma amylin >100 times above normal. Similar doses of adrenomedullin increased TZR density modestly but without effect on U(Caex), whereas CGRP did not alter TZR density and tended to increase U(Caex). We propose that U(Caex) and TZR density in the rat kidney are regulated by rat amylin but not by rat calcitonin.
3
Hendrikse, Erica R., Rebekah L. Bower, Debbie L. Hay, and Christopher S. Walker. "Molecular studies of CGRP and the CGRP family of peptides in the central nervous system." Cephalalgia 39, no. 3 (March 22, 2018): 403–19. http://dx.doi.org/10.1177/0333102418765787.
Full textAbstract:
Background Calcitonin gene-related peptide is an important target for migraine and other painful neurovascular conditions. Understanding the normal biological functions of calcitonin gene-related peptide is critical to understand the mechanisms of calcitonin gene-related peptide-blocking therapies as well as engineering improvements to these medications. Calcitonin gene-related peptide is closely related to other peptides in the calcitonin gene-related peptide family of peptides, including amylin. Relatedness in peptide sequence and in receptor biology makes it difficult to tease apart the contributions that each peptide and receptor makes to physiological processes and to disorders. Summary The focus of this review is the expression of calcitonin gene-related peptide, related peptides and their receptors in the central nervous system. Calcitonin gene-related peptide is expressed throughout the nervous system, whereas amylin and adrenomedullin have only limited expression at discrete sites in the brain. The components of two receptors that respond to calcitonin gene-related peptide, the calcitonin gene-related peptide receptor (calcitonin receptor-like receptor with receptor activity-modifying protein 1) and the AMY1 receptor (calcitonin receptor with receptor activity-modifying protein 1), are expressed throughout the nervous system. Understanding expression of the peptides and their receptors lays the foundation for more deeply understanding their physiology, pathophysiology and therapeutic use.
4
Zaidi, M., S. D. Brain, J. R. Tippins, V. Di Marzo, B. S. Moonga, T. J. Chambers, H. R. Morris, and I. MacIntyre. "Structure-activity relationship of human calcitonin-gene-related peptide." Biochemical Journal 269, no. 3 (August 1, 1990): 775–80. http://dx.doi.org/10.1042/bj2690775.
Full textAbstract:
The calcitonin-calcitonin-gene-related peptide (CGRP) gene complex encodes a small family of peptides: calcitonin, CGRP and katacalcin. Calcitonin is a circulating hormone that prevents skeletal breakdown by inhibiting the resorption of bone by osteoclasts. CGRP, a potent vasodilator, is involved in normal regulation of blood flow. The calcitonins structurally resemble the CGRP peptides, and both are known to cross-react at each others' receptors. The present study was undertaken to examine the structural prerequisites for biological activity of the intact CGRP molecule. We therefore prepared eight chymotryptic and tryptic fragments of CGRP and synthesized its acetylated and S-carboxyamidomethylcysteinyl analogues. The analogues were purified by h.p.l.c. and their structures were confirmed by fast-atom bombardment mass spectrometry. We have examined the effects of structurally modified analogues and fragments of human CGRP in a calcitonin-receptor-mediated assay, the osteoclast bone resorption assay, and in one or two CGRP-receptor-mediated assays, the rabbit skin blood flow assay and the oedema formation assay. The results showed that (1) in the osteoclast bone resorption assay, both CGRP peptides, alpha and beta, were equipotent, and were both at least 1000-fold were both approx. 1000-fold more potent than salmon calcitonin; human calcitonin had no effect; (3) the bis- and N-acetylated CGRP analogues retained reduced levels of biological activity in all assays, whereas S-carboxyamidomethylcysteinyl-human CGRP was without activity; and (4) all tryptic and chymotryptic fragments of CGRP were without biological activity, with the exception of hCGRP-(Ala1-Lys35): this fragment had much reduced activity compared with the intact peptide in inhibiting osteoclastic bone resorption and increasing blood flow in the rabbit skin. The results suggest that: (1) calcitonin and CGRP act at distinct receptors to mediate different physiological effects; (2) minor amino acid substitutions, as between the alpha and beta forms of CGRP (these two forms have 94% structural similarity) do not result in differences in biological activity; (3) the intact peptide is required for full biological activity of the CGRP molecule, and even the loss of two amino acids at the C-terminus of the molecule results in a marked decrease in activity; (4) the disulphide bridge appears to play an important role in the interaction of the intact CGRP molecule with its receptor; and (5) the C-terminal region is probably necessary for the peptide to assume the right conformation in the interaction with the receptor.
5
Magalhães, Patrícia K. R., Margaret de Castro, Lucila L. K. Elias, and Léa M. Z. Maciel. "Carcinoma medular de tireóide: da definição às bases moleculares." Arquivos Brasileiros de Endocrinologia & Metabologia 47, no. 5 (October 2003): 515–28. http://dx.doi.org/10.1590/s0004-27302003000500004.
Full textAbstract:
O carcinoma medular de tireóide (CMT) é um tumor maligno raro com origem nas células parafoliculares da tireóide, tendo como principal produto secretório a calcitonina. Representa 3 a 10% de todos os tumores tireoidianos e é responsável por um grande número de mortes em portadores de câncer de tireóide. Em 75-90% dos pacientes, o CMT ocorre de forma esporádica e, nos demais casos, é uma doença hereditária autossômica dominante com alto grau de penetrância e variabilidade de expressão, podendo fazer parte de 3 síndromes distintas: neoplasia endócrina múltipla (NEM) 2A, NEM 2B ou CMT familiar. As diferentes formas clínicas do CMT, principalmente as hereditárias, estão relacionadas com mutações no proto-oncogene RET, as quais resultam em ativação constitutiva do receptor de membrana tirosina-quinase RET. A distinção entre estas formas é de extrema relevância clínica por causa das diferenças apresentadas entre elas em termos de prognóstico e pela necessidade de um rastreamento familiar, aconselhamento genético e seguimento das formas hereditárias. A eficiência do rastreamento genético, pela pesquisa de mutações no proto-oncogene RET, está bem estabelecida no diagnóstico e na identificação de portadores assintomáticos das formas hereditárias de CMT, permitindo uma intervenção cirúrgica precoce e efetiva, reduzindo a morbidade e a mortalidade associadas a esta doença.
6
Smith, D. M., H. A. Coppock, D. J. Withers, A. A. Owji, D. L. Hay, T. P. Choksi, P. Chakravarty, S. Legon, and D. R. Poyne. "Adrenomedullin: receptor and signal transduction." Biochemical Society Transactions 30, no. 4 (August 1, 2002): 432–37. http://dx.doi.org/10.1042/bst0300432.
Full textAbstract:
Adrenomedullin is a vascular tissue peptide and a member of the calcitonin family of peptides, which includes calcitonin, calcitonin-gene-related peptide (CGRP) and amylin. Its many biological actions are mediated via CGRP type 1 (CGRP1) receptors and by specific adrenomedullin receptors. Although the pharmacology of these receptors is distinct, they are both represented in molecular terms by the type II family G-protein-coupled receptor, calcitonin-receptor-like receptor (CRLR). The specificity here is defined by co-expression of receptor-activity-modifying proteins (RAMPs). CGRP1 receptors are represented by CRLR and RAMP1, and specific adrenomedullin receptors by CRLR and RAMP2 or 3. Here we discuss how CRLR/RAMP2 relates to adrenomedullin binding, pharmacology and pathophysiology, and how chemical cross-linking of receptor-ligand complexes in tissue relates to that in CRLR/RAMP2-expressing cells. CRLR, like other type II family G-protein-coupled receptors, signals via Gs and adenylate cyclase activation. We demonstrated that adrenomedullin signalling in cell lines expressing specific adrenomedullin receptors followed this expected pattern.
7
Oliver, K. R. "CGRP Receptor Family and Accessory Protein Localization: Implications for Predicted Function." Scientific World JOURNAL 1 (2001): 10. http://dx.doi.org/10.1100/tsw.2001.431.
Full textAbstract:
Calcitonin gene-related peptide (CGRP), adrenomedullin, amylin, and calcitonin are functionally related neuropeptides. Certain of these peptides mediate their action through receptors which have common components, such as the receptor activity modifying proteins (RAMPs) and CGRP-receptor component protein, as well as possibly through other distinct receptors. Specifically, the molecular pharmacology of CGRP and adrenomedullin is determined by coexpression of one of three receptor activity-modifying proteins (RAMPs) with calcitonin receptor-like receptor (CRLR). Additionally, through formation of another hetero-oligomer, RAMPs also govern the pharmacology of the calcitonin receptor, which in association with RAMP1 or RAMP3, binds amylin with high affinity. We have used multiple approaches to discern the regional and cellular expression of these various receptor components and binding sites for the above neuropeptides in multiple species and in different tissues. Techniques applied include in situ hybridization, immunohistochemistry and radioligand autoradiography. These data allow further understanding of both the complexity of receptor-receptor component and receptor-ligand interactions in vivo. Interestingly, these localization data suggest that RAMPs may interact with receptors additional to those already identified for the CGRP family and may be involved in binding innate neuropeptides or other neurotransmitters which are not members of the calcitonin gene-related peptide fam
8
Razzaque, Z., D. Shaw, M. Bock, L. Maskell, J. Pickard, D. Sirinathsinghji, and J. Longmore. "Study of Cgrp-Receptors in Human Isolated Middle Meningeal Arteries Using Bibn4096Bs, Compound 1, and HαCgrp(8-37)." Scientific World JOURNAL 1 (2001): 17. http://dx.doi.org/10.1100/tsw.2001.437.
Full textAbstract:
Calcitonin, CGRP, adrenomedullin, and amylin require both CRLR (calcitonin-gene receptor like receptor) and receptor activity modifying proteins (RAMP1, RAMP2, and RAMP3) in different combinations for expression of selective, functional receptors[1]. We investigated whether the antagonists BIBN4096BS[2], Compound 1 (WO98/11128, [3]), and CGRP(8-37) are functionally selective for CGRP receptors in human middle meningeal arteries (HMMA).
9
Warfvinge, Karin, and Lars Edvinsson. "Distribution of CGRP and CGRP receptor components in the rat brain." Cephalalgia 39, no. 3 (August 31, 2017): 342–53. http://dx.doi.org/10.1177/0333102417728873.
Full textAbstract:
Background Calcitonin gene-related peptide and its receptor, consisting of receptor activity-modifying protein 1 and calcitonin receptor-like receptor, are of considerable interest because of the role they play in migraine and recently developed migraine therapies. Methods To better understand the function of this neuropeptide, we used immunohistochemistry to determine a detailed distribution of calcitonin gene-related peptide, receptor activity-modifying protein 1 and calcitonin receptor-like receptor in the rat brain in a region of 0.5–1.5 mm lateral to the midline. We found calcitonin gene-related peptide immunoreactivity in most of the neurons of the cerebral cortex, hippocampus, cerebellum, thalamic nuclei, hypothalamic nuclei and brainstem nuclei. In contrast, receptor activity-modifying protein 1 and calcitonin receptor-like receptor immunoreactivity were found almost exclusively in the neuronal processes in the investigated regions. Conclusion Overall, the degree of expression of calcitonin gene-related peptide and calcitonin gene-related peptide receptor components in the central nervous system is astonishingly complex and suggestive of many different brain functions, including a possible role in migraine. However, currently, the presence of calcitonin gene-related peptide and the nature of its receptors throughout the brain is an enigma yet to be solved.
10
Faria, Sara Socorro, and Pedro Leme Silva Pedro Leme Silva Pedro Leme Silva. "Revisão Sistemática sobre Tratamento Medicamentoso para Dor no Membro Fantasma." Revista Neurociências 22, no. 2 (June 30, 2014): 177–88. http://dx.doi.org/10.34024/rnc.2014.v22.8091.
Full textAbstract:
Objetivo. Realizar revisão sistemática da literatura sobre as possíveis condutas farmacológicas utilizadas para tratamento da dor do membro fantasma. Método. A estratégia de busca foi realizada nas bases de dados eletrônicas Cochrane, Pubmed e Lilacs através da consulta de descritores específicos. A busca consistiu de artigos apresentados na íntegra, escritos em inglês ou espanhol, adultos humanos de ambos os sexos, publicados no período de 1990 a 2012. Resultados. Após a aplicação dos critérios de exclusão, foram selecionados 20 artigos. Através da análise, verificou-se que existem possibilidades terapêuticas positivas a curto prazo a serem utilizadas, dentre elas destacam-se os opióides, gabapentina e a quetamina. A morfina (oral e intravenosa) foi eficaz na diminuição da intensidade da dor a curto-prazo. Com exceção da memantina, os antagonistas do receptor NMDA, morfina e a quetamina apresentaram efeitos analgésicos. Entretanto, os resultados obtidos com a gabapentina em termos de alívio da dor não foram significativos. O direcionamento da eficácia da calcitonina e dextrometorfano necessitam maiores esclarecimentos. Conclusão. A morfina e a quetamina demonstraram ser eficazes como analgésicos de curta duração. Maiores estudos tornam-se necessários para esclarecer os reais benefícios da amitriptilina, o cloridrato de tramadol, memantina e a toxina botulínica. Intervenções em pesquisas com maior número de participantes são importantes, a fim de estabelecer recomendações na prática terapêutica.
11
Tzabazis, Alexander, Jordan Mechanic, James Miller, Michael Klukinov, Conrado Pascual, Neil Manering, Dean S. Carson, et al. "Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders." Cephalalgia 36, no. 10 (July 20, 2016): 943–50. http://dx.doi.org/10.1177/0333102415618615.
Full textAbstract:
Aims Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain. Methods Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene-related peptide release from dural nociceptors were investigated using isolated rat dura mater. Results Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene-related peptide release from dural nociceptors. Conclusion Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders.
12
Haanes, Kristian A., Alejandro Labastida-Ramírez, Frank W. Blixt, Eloisa Rubio-Beltrán, Clemens M. Dirven, Alexander HJ Danser, Lars Edvinsson, and Antoinette MaassenVanDenBrink. "Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models." Cephalalgia 39, no. 11 (May 19, 2019): 1421–34. http://dx.doi.org/10.1177/0333102419851810.
Full textAbstract:
Background The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine. Objective We aimed to explore purinergic receptors as potential anti-migraine targets. Methods We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents. Results We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction in vitro; b) reduced dural artery dilation following periarterial electrical stimulation in vivo and c) a reduction of CGRP release from both the dura and the trigeminal ganglion in situ. Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation. Conclusion Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.
13
Christopoulos, George, Patrick M. Sexton, George Paxinos, Xu-Feng Huang, Kevin Beaumont, and Arthur W. Toga. "Comparative distribution off receptors for amylin and the related peptides calcitonin gene related peptide and calcitonin in rat and monkey brain." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 1037–41. http://dx.doi.org/10.1139/y95-146.
Full textAbstract:
The distribution of amylin receptors (125I-labelled rat amylin) in brains of rat and monkey were mapped and compared with the distribution of receptors for calcitonin (CT) (125I-labelled salmon CT) and calcitonin gene related peptide (CGRP) (rat, 125I-labelled rat CGRPα; monkey, 125-labelled human CGRPα). In rat, amylin receptors were discretely distributed with the highest receptor densities found in mid-caudal accumbens nucleus, parts of the bed nucleus of the stria terminalis, amygdala, and hypothalamus. Moderate to high densities of binding also occurred in the area postrema, subfornical organ, vascular organ of the lamina terminalis, locus ceruleus, dorsal raphe, and caudal solitary tract nucleus. In monkey, the distribution of amylin binding sites was similar, although the highest densities of receptors were in the hypothalamus, with relatively fewer sites present in the accumbens nucleus. In rat, the distribution of amylin receptors formed a subset of the receptor distributions for 125I-labelled salmon CT and 125I-labelled rat CGRPα. In contrast, in monkey, although the amyiin receptors again formed a subset of the binding sites identified with 125I-labelled salmon CT, mere was very little overlap with the pattern of CGRP receptor distribution. This suggests that the specificity profile of amylin receptors in primates differs from that of amylin receptors in the rat, with CGRPα having relatively lower affinity for the primate amylin receptors.Key words: amylin, calcitonin, calcitonin gene related peptide, receptor, rat, monkey.
14
Muff, Roman, Walter Born, and Jan A. Fischer. "Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin: homologous peptides, separate receptors and overlapping biological actions." European Journal of Endocrinology 133, no. 1 (July 1995): 17–20. http://dx.doi.org/10.1530/eje.0.1330017.
Full textAbstract:
Muff R, Born W, Fischer JA. Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin: homologous peptides, separate receptors and overlapping biological actions. Eur J Endocrinol 1995;133:17–20. ISSN 0804–4643 Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin are structurally related peptides with N-terminal 6–7 amino acid ring structures linked by a disulfide bridge and with amidated C-termini. Among the related bioactive peptides, the structures of the calcitonin receptor and subtypes thereof have been identified so far through molecular cloning. Cross-reaction between receptors of calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin, as well as overlapping biological actions, anticipate that the respective receptors belong to a family of G-protein-coupled receptors that include those of parathyroid hormone, secretin and vasointestinal peptide. Jan A Fischer, Klinik Balgrist, Forchstrasse 340, CH-8008 Zurich, Switzerland
15
Lee, Sangmin. "Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors." Biomolecules 11, no. 9 (September 15, 2021): 1364. http://dx.doi.org/10.3390/biom11091364.
Full textAbstract:
The calcitonin and amylin receptors (CTR and AMY receptors) are the drug targets for osteoporosis and diabetes treatment, respectively. Salmon calcitonin (sCT) and pramlintide were developed as peptide drugs that activate these receptors. However, next-generation drugs with improved receptor binding profiles are desirable for more effective pharmacotherapy. The extracellular domain (ECD) of CTR was reported as the critical binding site for the C-terminal half of sCT. For the screening of high-affinity sCT analog fragments, purified CTR ECD was used for fluorescence polarization/anisotropy peptide binding assay. When three mutations (N26D, S29P, and P32HYP) were introduced to the sCT(22–32) fragment, sCT(22–32) affinity for the CTR ECD was increased by 21-fold. CTR was reported to form a complex with receptor activity-modifying protein (RAMP), and the CTR:RAMP complexes function as amylin receptors with increased binding for the peptide hormone amylin. All three types of functional AMY receptor ECDs were prepared and tested for the binding of the mutated sCT(22–32). Interestingly, the mutated sCT(22–32) also retained its high affinity for all three types of the AMY receptor ECDs. In summary, the mutated sCT(22–32) showing high affinity for CTR and AMY receptor ECDs could be considered for developing the next-generation peptide agonists.
16
Oliver, Kevin R., Anna Wainwright, Lars Edvinsson, John D. Pickard, and Raymond G. Hill. "Immunohistochemical Localization of Calcitonin Receptor–Like Receptor and Receptor Activity–Modifying Proteins in the Human Cerebral Vasculature." Journal of Cerebral Blood Flow & Metabolism 22, no. 5 (May 2002): 620–29. http://dx.doi.org/10.1097/00004647-200205000-00014.
Full textAbstract:
Calcitonin gene-related peptide and adrenomedullin belong to a structurally related neuropeptide family and are potent vasodilators expressed in the trigeminovascular system. The molecular identity of receptors for these proteins has only recently been elucidated. Central to functional binding of these neuropeptides is the G-protein–coupled receptor, the calcitonin receptor–like receptor (CRLR), whose cell surface expression and pharmacology is determined by coexpression of a receptor activity-modifying protein (RAMP). CRLR combined with RAMP1 binds calcitonin gene-related peptide with high affinity, whereas CRLR coexpression with RAMP2 or −3 confers high-affinity binding of adrenomedullin. The authors investigated the expression of these receptor components in human cerebral vasculature to further characterize neuropeptide receptor content and the potential functions of these receptors. Localization has been carried out using specific antisera raised against immunogenic peptide sequences that were subsequently applied using modern immunohistochemical techniques and confocal microscopy. The results are the first to show the presence of these receptor component proteins in human middle meningeal, middle cerebral, pial, and superficial temporal vessels, and confirm that both calcitonin gene-related peptide and adrenomedullin receptors may arise from the coassembly of RAMPs with CRLR in these vessel types. These novel data advance the understanding of the molecular function of the trigeminovascular system, its potential role in vascular headache disorders such as migraine, and may lead to possible ways in which future synthetic ligands may be applied to manage these disorders.
17
Prado, M. A., B. Evans-Bain, and I. M. Dickerson. "Receptor component protein (RCP): a member of a multi-protein complex required for G-protein-coupled signal transduction." Biochemical Society Transactions 30, no. 4 (August 1, 2002): 460–64. http://dx.doi.org/10.1042/bst0300460.
Full textAbstract:
The calcitonin-gene-related peptide (CGRP) receptor component protein (RCP) is a 148-amino-acid intracellular protein that is required for G-protein-coupled signal transduction at receptors for the neuropeptide CGRP. RCP works in conjunction with two other proteins to constitute a functional CGRP receptor: calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying protein 1 (RAMP1).CRLR has the stereotypical seven-transmembrane topology of a G-protein-coupled receptor; it requires RAMP1 for trafficking to the cell surface and for ligand specificity, and requires RCP for coupling to the cellular signal transduction pathway. We have made cell lines that expressed an antisense construct of RCP and determined that CGRP-mediated signal transduction was reduced, while CGRP binding was unaffected. Furthermore, signalling at two other endogenous G-protein-coupled receptors was unaffected, suggesting that RCP was specific for a limited subset of receptors.
18
Warfvinge, Karin, Diana N. Krause, Aida Maddahi, Anne-Sofie Grell, Jacob CA Edvinsson, Kristian A. Haanes, and Lars Edvinsson. "Oxytocin as a regulatory neuropeptide in the trigeminovascular system: Localization, expression and function of oxytocin and oxytocin receptors." Cephalalgia 40, no. 12 (June 2, 2020): 1283–95. http://dx.doi.org/10.1177/0333102420929027.
Full textAbstract:
Background Recent clinical findings suggest that oxytocin could be a novel treatment for migraine. However, little is known about the role of this neuropeptide/hormone and its receptor in the trigeminovascular pathway. Here we determine expression, localization, and function of oxytocin and oxytocin receptors in rat trigeminal ganglia and targets of peripheral (dura mater and cranial arteries) and central (trigeminal nucleus caudalis) afferents. Methods The methods include immunohistochemistry, messenger RNA measurements, quantitative PCR, release of calcitonin gene-related peptide and myography of arterial segments. Results Oxytocin receptor mRNA was expressed in rat trigeminal ganglia and the receptor protein was localized in numerous small to medium-sized neurons and thick axons characteristic of A∂ sensory fibers. Double immunohistochemistry revealed only a small number of neurons expressing both oxytocin receptors and calcitonin gene-related peptide. In contrast, double immunostaining showed expression of the calcitonin gene-related peptide receptor component receptor activity-modifying protein 1 and oxytocin receptors in 23% of the small cells and in 47% of the medium-sized cells. Oxytocin immunofluorescence was observed only in trigeminal ganglia satellite glial cells. Oxytocin mRNA was below detection limit in the trigeminal ganglia. The trigeminal nucleus caudalis expressed mRNA for both oxytocin and its receptor. K+-evoked calcitonin gene-related peptide release from either isolated trigeminal ganglia or dura mater and it was not significantly affected by oxytocin (10 µM). Oxytocin directly constricted cranial arteries ex vivo (pEC50 ∼ 7); however, these effects were inhibited by the vasopressin V1A antagonist SR49059. Conclusion Oxytocin receptors are extensively expressed throughout the rat trigeminovascular system and in particular in trigeminal ganglia A∂ neurons and fibers, but no functional oxytocin receptors were demonstrated in the dura and cranial arteries. Thus, circulating oxytocin may act on oxytocin receptors in the trigeminal ganglia to affect nociception transmission. These effects may help explain hormonal influences in migraine and offer a novel way for treatment.
19
Nicholson, G. C., C. S. D'Santos, T. Evans, J. M. Moseley, B. E. Kemp, V. P. Michelangeli, and T. J. Martin. "Human placental calcitonin receptors." Biochemical Journal 250, no. 3 (March 15, 1988): 877–82. http://dx.doi.org/10.1042/bj2500877.
Full textAbstract:
Receptors for the hypocalcaemic hormone, calcitonin (CT), have been identified in a membrane fraction prepared from term human placentae. Binding of 125I-labelled salmon CT (125I-sCT) to the membranes was time- and temperature-dependent, saturable (Bmax. 58 +/- 11 fmol/mg of protein), of high affinity (Kd 80 +/- 21 pM) and poorly reversible. Species-specific CTs and CT analogues competed for 125I-sCT binding with potencies proportional to their known biological potencies. Various unrelated peptide hormones did not compete, indicating that receptor binding was specific for CT. Photoaffinity labelling using a derivatized biologically active sCT analogue, [Arg11,18,3-nitrophenylazide-Lys14]sCT, identified a receptor component of Mr approximately 85,000, comparable with findings in osteoclasts and other target cells. The presence of CT receptors in the human placenta supports other evidence that CT may have a role in the regulation of placental function.
20
Nguyen, Cathy, Anne-Marie Coelho, Eileen Grady, Steven J. Compton, John L. Wallace, Morley D. Hollenberg, Nicolas Cenac, et al. "Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism." Canadian Journal of Physiology and Pharmacology 81, no. 9 (September 1, 2003): 920–27. http://dx.doi.org/10.1139/y03-080.
Full textAbstract:
Proteinase-activated receptor-2 (PAR2) activation induces colonic inflammation by an unknown mechanism. We hypothesized that PAR2 agonists administered intracolonically in mice induce inflammation via a neurogenic mechanism. Pretreatment of mice with neurokinin-1 and calcitonin-gene-related peptide (CGRP) receptor antagonists or with capsaicin showed attenuated PAR2-agonist-induced colitis. Immunohistochemistry demonstrated a differential expression of a marker for the type-1 CGRP receptor during the time course of PAR2-agonist-induced colitis, further suggesting a role for CGRP. We conclude that PAR2-agonist-induced intestinal inflammation involves the release of neuropeptides, which by acting on their receptors cause inflammation. These results implicate PAR2 as an important mediator of intestinal neurogenic inflammation.Key words: trypsin, proteinase-activated receptor-2, colitis, neurogenic inflammation, substance P, neurokinin-1 receptors, calcitonin-gene-related peptide.
21
Bower, Rebekah L., Sajedeh Eftekhari, Henry J. Waldvogel, Richard L. M. Faull, János Tajti, Lars Edvinsson, Debbie L. Hay, and Christopher S. Walker. "Mapping the calcitonin receptor in human brain stem." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 310, no. 9 (May 1, 2016): R788—R793. http://dx.doi.org/10.1152/ajpregu.00539.2015.
Full textAbstract:
The calcitonin receptor (CTR) is relevant to three hormonal systems: amylin, calcitonin, and calcitonin gene-related peptide (CGRP). Receptors for amylin and calcitonin are targets for treating obesity, diabetes, and bone disorders. CGRP receptors represent a target for pain and migraine. Amylin receptors (AMY) are a heterodimer formed by the coexpression of CTR with receptor activity-modifying proteins (RAMPs). CTR with RAMP1 responds potently to both amylin and CGRP. The brain stem is a major site of action for circulating amylin and is a rich site of CGRP binding. This study aimed to enhance our understanding of these hormone systems by mapping CTR expression in the human brain stem, specifically the medulla oblongata. Widespread CTR-like immunoreactivity was observed throughout the medulla. Dense CTR staining was noted in several discrete nuclei, including the nucleus of the solitary tract, the hypoglossal nucleus, the cuneate nucleus, spinal trigeminal nucleus, the gracile nucleus, and the inferior olivary nucleus. CTR staining was also observed in the area postrema, the lateral reticular nucleus, and the pyramidal tract. The extensive expression of CTR in the medulla suggests that CTR may be involved in a wider range of functions than currently appreciated.
22
Aiyar, Nambi. "Overview of Calcitonin Gene-Related Peptide and Its Receptor." Scientific World JOURNAL 1 (2001): 1. http://dx.doi.org/10.1100/tsw.2001.401.
Full textAbstract:
Calcitonin Gene-Related Peptide (CGRP), a 37 amino acid peptide identified as the alternately spliced gene product of calcitonin gene, is a sensory neuropeptide with potent cardiovascular effects. CGRP is distributed throughout the central and peripheral nervous systems and possesses diverse biological actions. CGRP has been suggested to play a role in diseases such as migraine, diabetes, pain, and inflammation. Two forms of CGRP (alpha and beta) that differ in three amino acids have been identified and are encoded by different genes. Based on the differential biological activities of various CGRP analogs, the CGRP receptors have been classified into CGRP1 and CGRP2. Structure-activity studies of CGRP analogs showed that the C- and N-terminal regions of the peptide interact independently with their receptors. While C-terminal peptide, CGRP (8-37) behaves as a CGRP1 receptor antagonist, N-terminal peptide CGRP (1-12) behaves as a weak agonist. Structural modifications of CGRP(28-37) have yielded micromolar to nanomolar affinity ligands. CGRP receptor belongs to the calcitonin receptor like receptor (CRLR) family of G-protein-coupled receptors and has been shown to require a single transmembrane domain protein called receptor activity modifying protein-1 (RAMP1) for its functional expression as well as activity. Human, rat, and porcine CRLRs have been cloned and characterized. Currently, the major focus is on the identification of potent and specific nonpeptide antagonists for this receptor in order to understand the physiological and pathophysiological role of this peptide.
23
Zaidi, M., A. Patchell, H. K. Datta, and I. MacIntyre. "UNCOUPLING OF RECEPTOR-MEDIATED CELLULAR RESPONSES BY IONIC LITHIUM." Journal of Endocrinology 123, no. 2 (November 1989): R5—R7. http://dx.doi.org/10.1677/joe.0.123r005.
Full textAbstract:
ABSTRACT The propensity of ionic lithium to interfere with the coupling of receptors to guanine nucleotide binding proteins (G-proteins) has only recently been investigated using rat cortical membranes. In the present study we have used intact isolated osteoclasts to investigate lithium-induced uncoupling of the receptor-mediated actions of calcitonin. All actions of calcitonin on the osteoclast were abolished by ionic lithium. We believe that the cation prevents signal transduction by inhibiting G protein-receptor interaction, the first step in intracellular signalling.
24
Barwell, James, Joseph J. Gingell, Harriet A. Watkins, Julia K. Archbold, David R. Poyner, and Debbie L. Hay. "Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?" British Journal of Pharmacology 166, no. 1 (April 10, 2012): 51–65. http://dx.doi.org/10.1111/j.1476-5381.2011.01525.x.
Full text
25
Barwell, James, Mark Wheatley, Alex C. Conner, Bruck Taddese, Shabana Vohra, Christopher A. Reynolds, and David R. Poyner. "The activation of the CGRP receptor." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 180–84. http://dx.doi.org/10.1042/bst20120251.
Full textAbstract:
The CGRP (calcitonin gene-related peptide) receptor is a family B GPCR (G-protein-coupled receptor). It consists of a GPCR, CLR (calcitonin receptor-like receptor) and an accessory protein, RAMP1 (receptor activity modifying protein 1). RAMP1 is needed for CGRP binding and also cell-surface expression of CLR. CLR is an example of a family B GPCR. Unlike family A GPCRs, little is known about how these receptors are activated by their endogenous ligands. This review considers what is known about the activation of family B GPCRs and then considers how this might be applied to CLR, particularly in light of new knowledge of the crystal structures of family A GPCRs.
26
Qing, Xin, John Svaren, and Ingegerd M. Keith. "mRNA expression of novel CGRP1 receptors and their activity-modifying proteins in hypoxic rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 280, no. 3 (March 1, 2001): L547—L554. http://dx.doi.org/10.1152/ajplung.2001.280.3.l547.
Full textAbstract:
Calcitonin gene-related peptide (CGRP) is a potent vasodilator. Our group has reported that exogenous CGRP may prevent or reverse hypoxic pulmonary hypertension in rats. The vasodilatory action of CGRP is mediated primarily by CGRP1 receptors. The calcitonin receptor-like receptor (CRLR) and the orphan receptor RDC-1 have been proposed as CGRP1 receptors, and recent evidence suggests that CRLR can function as either a CGRP1 receptor or an adrenomedullin (ADM) receptor. Receptor activity-modifying proteins (RAMPs) determine the ligand specificity of CRLR: coexpression of CRLR and RAMP1 results in a CGRP1 receptor, whereas coexpression of CRLR and RAMP2 or -3 results in an ADM receptor. We used qualitative, semiquantitative, and real-time quantitative RT-PCR to detect and quantitate the relative expression of these agents in the lungs of rats exposed to normoxia ( n = 3) and 1 and 2 wk of chronic hypobaric hypoxia (barometric pressure 380 mmHg, equivalent to an inspired O2 level of 10%; n = 3/time period). Our results show upregulation of RDC-1, RAMP1, and RAMP3 mRNAs in hypoxic rat lung and no change in CRLR and RAMP2 mRNAs. These findings support a functional role for CGRP and ADM receptors in regulating the adult pulmonary circulation.
27
Gydesen, Sofie, Kim Vietz Andreassen, Sara Toftegaard Hjuler, Jane Marie Christensen, Morten Asser Karsdal, and Kim Henriksen. "KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight." American Journal of Physiology-Endocrinology and Metabolism 310, no. 10 (May 15, 2016): E821—E827. http://dx.doi.org/10.1152/ajpendo.00514.2015.
Full textAbstract:
This study aims to elucidate the mechanism behind the potent weight loss induced by dual amylin and calcitonin receptor agonists (DACRA) through comparison of the novel DACRA KBP-088 with the amylinomimetic davalintide with regard to in vitro receptor pharmacology and in vivo efficacy on food intake and body weight. KBP-088 and davalintide were tested for their ability to activate the amylin and calcitonin receptors as function of dose and time. Two doses of KBP-088 (1.67 and 5.0 μg/kg) were compared with similar davalintide doses in high-fat diet (HFD)-fed rats receiving subcutaneous dosing once daily for 62 days. Glucose tolerance was assessed after 3 and 7 wk of treatment. KBP-088 demonstrated activation of amylin and calcitonin receptors and prolonged receptor activation compared with davalintide as well as a potent reduction of acute food intake. KBP-088 transiently reduced food intake and induced and notably sustained a significant ∼16% vehicle-corrected weight loss without significant weight loss in the calorie-restricted control groups. Additionally, KBP-088 reduced white adipose tissues and adipocyte hypertrophy. Finally, KBP-088 alleviated hyperinsulinemia and improved oral glucose tolerance even with significantly lower insulin levels after 3 and 7 wk of treatment. KBP-088 is a potent amylin and calcitonin receptor agonist with prolonged receptor activation compared with davalintide. Moreover, KBP-088 induced and sustained significant weight loss and reduced overall adiposity and adipocyte hypertrophy in HFD rats. Finally, KBP-088 improved oral glucose tolerance and alleviated hyperinsulinemia, underscoring the potential of KBP-088 as an antiobesity agent with benefits on glucose control.
28
Egerton, M., M. Needham, S. Evans, A. Millest, G. Cerillo, J. McPheat, M. Popplewell, D. Johnstone, and M. Hollis. "Identification of multiple human calcitonin receptor isoforms: heterologous expression and pharmacological characterization." Journal of Molecular Endocrinology 14, no. 2 (April 1995): 179–89. http://dx.doi.org/10.1677/jme.0.0140179.
Full textAbstract:
ABSTRACT The human breast carcinoma cell line T47D is known to express high-affinity calcitonin receptors (CTRs). PCR amplification of the CTR cDNA from T47D mRNA resulted in the identification of two different cDNAs that encode distinct receptor isoforms, hαCTR and hβCTR. The two cDNAs are identical except that the hαCTR cDNA contains a 48 bp insert sequence that encodes a 16 amino acid domain in the first cytosolic loop of the receptor. Stable transfection of each receptor cDNA into murine erythroleukaemia (MEL) cells resulted in the expression of receptors with high affinity for radiolabelled salmon calcitonin (hαCTR Kd 0·09 nm, hβCTR Kd 0·12 nm). Ligand competition binding studies did not reveal any significant pharmacological difference between the receptor isoforms. In transfected MEL cells and COS-1 cells the hβCTR isoform was expressed at tenfold higher levels than the hαCTR. A reporter gene assay that monitored the coupling of CTR to adenylate cyclase by increases in β-galactosidase activity indicated that both receptors were able to stimulate cyclic AMP production in response to ligand binding.
29
Padilla, Benjamin E., Graeme S. Cottrell, Dirk Roosterman, Stella Pikios, Laurent Muller, Martin Steinhoff, and Nigel W. Bunnett. "Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and β-arrestins." Journal of Cell Biology 179, no. 5 (November 26, 2007): 981–97. http://dx.doi.org/10.1083/jcb.200704053.
Full textAbstract:
Although cell surface metalloendopeptidases degrade neuropeptides in the extracellular fluid to terminate signaling, the function of peptidases in endosomes is unclear. We report that isoforms of endothelin-converting enzyme-1 (ECE-1a–d) are present in early endosomes, where they degrade neuropeptides and regulate post-endocytic sorting of receptors. Calcitonin gene-related peptide (CGRP) co-internalizes with calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), β-arrestin2, and ECE-1 to early endosomes, where ECE-1 degrades CGRP. CGRP degradation promotes CLR/RAMP1 recycling and β-arrestin2 redistribution to the cytosol. ECE-1 inhibition or knockdown traps CLR/RAMP1 and β-arrestin2 in endosomes and inhibits CLR/RAMP1 recycling and resensitization, whereas ECE-1 overexpression has the opposite effect. ECE-1 does not regulate either the resensitization of receptors for peptides that are not ECE-1 substrates (e.g., angiotensin II), or the recycling of the bradykinin B2 receptor, which transiently interacts with β-arrestins. We propose a mechanism by which endosomal ECE-1 degrades neuropeptides in endosomes to disrupt the peptide/receptor/β-arrestin complex, freeing internalized receptors from β-arrestins and promoting recycling and resensitization.
30
Hay, D. L., G. Christopoulos, A. Christopoulos, and P. M. Sexton. "Amylin receptors: molecular composition and pharmacology." Biochemical Society Transactions 32, no. 5 (October 26, 2004): 865–67. http://dx.doi.org/10.1042/bst0320865.
Full textAbstract:
Several receptors which bind the hormone AMY (amylin) with high affinity have now been identified. The minimum binding unit is composed of the CT (calcitonin) receptor at its core, plus a RAMP (receptor activity modifying protein). The receptors have been named AMY1(a), AMY2(a) and AMY3(a) in accordance with the association of the CT receptor (CT(a)) with RAMP1, RAMP2 and RAMP3 respectively. The challenge is now to determine the localization and pharmacological nature of each of these receptors. Recent attempts to achieve these aims will be briefly discussed.
31
Hilton, JM, M. Dowton, S. Houssami, and PM Sexton. "Identification of key components in the irreversibility of salmon calcitonin binding to calcitonin receptors." Journal of Endocrinology 166, no. 1 (July 1, 2000): 213–26. http://dx.doi.org/10.1677/joe.0.1660213.
Full textAbstract:
This study investigates the poor reversibility of salmon calcitonin (sCT) binding to rat and human calcitonin receptors. Efficacy of CT and analogue peptides in (125)I-sCT binding competition and cAMP assays was compared with the dissociation kinetics of (125)I-labelled peptides. Assessment was performed on cells stably expressing either rat or human calcitonin receptors. Dissociation kinetics of the antagonists, sCT(8-32) and AC512, revealed that binding was rapidly and completely reversible at the receptors, despite high affinity binding, suggesting that poor reversibility required the active conformation of the receptor. G protein coupling was not essential as the dissociation kinetics of (125)I-sCT binding to cell membranes did not significantly alter in the presence of GTP gamma S. Time course experiments established that the transition to irreversibility was slow, while the reversible component of binding appeared to involve a single population of either receptor states or binding sites. Pre-bound (125)I-human CT dissociated rapidly from the receptors, indicating that not all agonists bound irreversibly. To identify structural features of sCT that contribute to its poor reversibility, dissociation kinetics of sCT analogues with various structural modifications were examined. Increasing truncation of N-terminal residues of sCT analogues led to a corresponding increase in the rate of peptide dissociation. Salmon CT peptides which had been substituted at the N-terminus by 13-21 residues of human CT (hCT) were equipotent with sCT in binding competition and cAMP accumulation assays but exhibited a dissociation rate similar to hCT. In contrast, despite lower affinity and efficacy at the receptors, the chimeric analogue sCT(1-16)-hCT(17-32) displayed poorly reversible binding, similar to sCT. Analysis of the dissociation kinetics of sCT analogues with differing alpha-helix forming potential indicated that the ability to form alpha-helical secondary structure was an important factor in the rate of ligand dissociation. We hypothesise that poor reversibility results from a conformational change in the receptor and/or ligand and that this is dependent, at least in part, on interaction with residues constrained within the alpha-helix of the peptide.
32
Nakano, Masaki, Mika Ikegame, Junko Igarashi-Migitaka, Yusuke Maruyama, Nobuo Suzuki, and Atsuhiko Hattori. "Suppressive effect of melatonin on osteoclast function via osteocyte calcitonin." Journal of Endocrinology 242, no. 2 (August 2019): 13–23. http://dx.doi.org/10.1530/joe-18-0707.
Full textAbstract:
Many studies have investigated the actions of melatonin on osteoblasts and osteoclasts. However, the underlying mechanisms, especially regarding osteocyte function, remain largely unknown. Therefore, this study aimed to clarify the underlying mechanisms of melatonin action on bone tissue via osteocyte function. Chick calvariae were employed as a model. In ovo injection of melatonin (5, 50 and 500 µg) dose-dependently decreased the mRNA expression levels of cathepsin K and matrix metalloproteinase 9 (MMP9) in chick calvariae without affecting the expression levels of receptor activator of NF-κB ligand or osteoprotegerin. Surprisingly enough, the expression of calcitonin mRNA in chick calvariae was significantly raised. After 3 days of in vitro treatment of melatonin (10−7 and 10−5 M) on newly hatched chick calvariae, both calcitonin mRNA expression in calvariae and the concentration of calcitonin in cultured medium were augmented in a dose-dependent manner, coincident with the decreased mRNA expression levels of cathepsin K and MMP9. Immunohistochemical analyses revealed expression of melatonin receptors and calcitonin by osteocytes buried in bone matrix. Moreover, the mRNA expression levels of melatonin receptors, calcitonin and sclerostin (a marker of osteocyte), were strongly and positively correlated. In conclusion, we demonstrated the expression of melatonin receptors and calcitonin expression in osteocytes for the first time and suggest a new mechanism underlying the suppressive effect of melatonin on osteoclasts via upregulation of calcitonin secretion by osteocytes.
33
Roehrkasse, Amanda M., Jason M. Booe, Sang-Min Lee, Margaret L. Warner, and Augen A. Pioszak. "Structure–function analyses reveal a triple β-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design." Journal of Biological Chemistry 293, no. 41 (August 23, 2018): 15840–54. http://dx.doi.org/10.1074/jbc.ra118.005062.
Full textAbstract:
The cardioprotective vasodilator peptide adrenomedullin 2/intermedin (AM2/IMD) and the related adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) signal through three heterodimeric receptors comprising the calcitonin receptor–like class B G protein–coupled receptor (CLR) and a variable receptor activity–modifying protein (RAMP1, -2, or -3) that determines ligand selectivity. The CGRP receptor (RAMP1:CLR) favors CGRP binding, whereas the AM1 (RAMP2:CLR) and AM2 (RAMP3:CLR) receptors favor AM binding. How AM2/IMD binds the receptors and how RAMPs modulate its binding is unknown. Here, we show that AM2/IMD binds the three purified RAMP–CLR extracellular domain (ECD) complexes with a selectivity profile that is distinct from those of CGRP and AM. AM2/IMD bound all three ECD complexes but preferred the CGRP and AM2 receptor complexes. A 2.05 Å resolution crystal structure of an AM2/IMD antagonist fragment–bound RAMP1–CLR ECD complex revealed that AM2/IMD binds the complex through a unique triple β-turn conformation that was confirmed by peptide and receptor mutagenesis. Comparisons of the receptor-bound conformations of AM2/IMD, AM, and a high-affinity CGRP analog revealed differences that may have implications for biased signaling. Guided by the structure, enhanced-affinity AM2/IMD antagonist variants were developed, including one that discriminates the AM1 and AM2 receptors with ∼40-fold difference in affinities and one stabilized by an intramolecular disulfide bond. These results reveal differences in how the three peptides engage the receptors, inform development of AM2/IMD-based pharmacological tools and therapeutics, and provide insights into RAMP modulation of receptor pharmacology.
34
Warfvinge, Karin, Lars Edvinsson, Darryl S. Pickering, and Majid Sheykhzade. "The Presence of Calcitonin Gene-Related Peptide and Its Receptors in Rat, Pig and Human Brain: Species Differences in Calcitonin Gene-Related Peptide Pharmacology." Pharmacology 104, no. 5-6 (2019): 332–41. http://dx.doi.org/10.1159/000502471.
Full textAbstract:
Aim: The aim of present study is to investigate the binding characteristics of non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists (i.e., gepants) in the brain membranes of rat, pig and human. Methods: The interaction of available gepants with the CGRP receptor was studied in the brain membranes of 3 different species using a radioligand competitive binding assay. In addition, the distribution of CGRP and its receptor component receptor activity modifying protein 1 (RAMP1) in rat cerebellum and cortex was explored using immunohistochemistry. Results: All gepants, except SB268262, displaced 100% of the radioligand specific binding in the brain tissue of all 3 species and showed highest affinity for CGRP receptors in human brain as compared to rat and pig brain membranes. Furthermore, radioligand binding studies revealed the presence of higher CGRP receptor density in human cerebellum compared to human cortex. The morphology, size and density of CGRP immunoreactive cells suggest that all cerebral cortical neurons were positive for CGRP. Slender receptor immunoreactive fibres were found spanning through the entire cortex. CGRP immunoreactivity was displayed in the cell soma of cerebellar Purkinje cells and in large neurons in the medial cerebellar nucleus. RAMP1 was found on the surface of the Purkinje cells and in parallel fibres, indicating presence in the granule cell axons. Conclusion: Cerebellum and cerebral cortex are rich in CGRP and CGRP receptors, which can be antagonized by gepants. However, all gepants display higher affinity for human CGRP receptors as compared to rat and pig CGRP receptors. Furthermore, human cerebellum seems to express higher density of CGRP receptors.
35
Kopruszinski, Caroline M., Peter Thornton, Joanne Arnold, Philip Newton, David Lowne, Edita Navratilova, Juliana Swiokla, et al. "Characterization and preclinical evaluation of a protease activated receptor 2 (PAR2) monoclonal antibody as a preventive therapy for migraine." Cephalalgia 40, no. 14 (November 1, 2020): 1535–50. http://dx.doi.org/10.1177/0333102420966581.
Full textAbstract:
Aim Migraine pain is thought to result from activation of meningeal nociceptors that might involve dural mast cell degranulation and release of proteases and pronociceptive mediators. Tryptase, the most abundant dural mast cell protease, has been demonstrated to stimulate dural mast cells, as well as trigeminal nociceptors by activating the protease activated receptor 2. Mast cell or neuronal protease activated receptors 2 may therefore represent a novel target for migraine treatment. In this study, we characterized and evaluated a novel protease activated receptor 2 monoclonal antibody as a preventive anti-migraine pain therapy in preclinical models. Methods Flow cytometry, immunocytochemistry, calcium imaging, Homogeneous Time Resolved Technology (HTRF) epitope competition assay and serum pharmacokinetic (PK) assay in rats were performed to confirm the activity, specificity and in vivo stability of PAR650097, a novel anti- protease activated receptor 2 monoclonal antibody. In vivo assessment was performed in female C57BL/6J mice by evaluation of PAR650097 in preventing cutaneous allodynia elicited by (a) supradural injection of the protease activated receptor 2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-amide trifluoroacetate (SLIGRL), or calcitonin gene-related (CGRP) peptide, and (b) induction of latent sensitization by priming with three daily episodes of restraint stress followed by challenge with a subthreshold inhalational exposure to umbellulone (UMB), a transient receptor potential ankyrin 1 (TRPA1) agonist. PAR650097 was administered as a pretreatment prior to the first restraint stress, umbellulone exposure, SLIGRL or calcitonin gene-related peptide injection. Additionally, fremanezumab, a calcitonin gene-related peptide antibody was administered as pre-treatment prior to supradural administration of calcitonin gene-related peptide or SLIGRL. Results In vitro, PAR650097 demonstrated rapid interaction with protease activated receptor 2, enabling it to fully inhibit protease-induced protease activated receptor 2 activation, in human and mouse cells, with high potency. Furthermore, PAR650097 was highly selective for protease activated receptor 2, demonstrating no affinity for protease activated receptor 1 protein and no functional effect on the activation of cellular protease activated receptor 1 with thrombin. In addition, PAR650097 had an acceptable PK profile, compatible with testing the effects of selective protease activated receptor 2 inhibition in vivo. In vivo, PAR650097 blocked cutaneous allodynia induced by either supradural SLIGRL or calcitonin gene-related peptide. Fremanezumab abolished cutaneous allodynia induced by supradural CGRP, and partially attenuated cutaneous allodynia induced by SLIGRL. Administration of PAR650097, before the first restraint stress episode, did not prevent the acute stress-induced cutaneous allodynia or restraint stress priming revealed by cutaneous allodynia induced by inhalational umbellulone. In contrast, PAR650097 prevented expression of cutaneous allodynia when given before the umbellulone challenge in restraint stress-primed animals. Conclusion PAR650097 specifically inhibits endogenously expressed protease activated receptor 2 in human and mouse cells with high potency. This antibody has an acceptable PK profile in rodents and effectively blocked SLIGR-induced cutaneous allodynia. PAR650097 additionally prevented cutaneous allodynia induced by supradural calcitonin gene-related peptide, indicating that the protease activated receptor 2 receptor is a downstream consequence of calcitonin gene-related peptide actions. Fremanezumab effectively blocked calcitonin gene-related peptide-induced cutaneous allodynia and only partially reduced cutaneous allodynia induced by a protease activated receptor 2 activator, suggesting both calcitonin gene-related peptide-dependent and -independent mechanisms in promoting migraine pain. While PAR650097 did not prevent stress-induced cutaneous allodynia or priming, it effectively prevented cutaneous allodynia induced by a TRPA1 agonist in animals with latent sensitization. Activation of protease activated receptor 2, therefore, contributes to both calcitonin gene-related peptide-dependent and -independent mechanisms in promoting migraine-like pain. Therapeutic targeting of protease activated receptor 2 receptors may represent an anti-migraine pain strategy with a potentially broad efficacy profile.
36
Zaidi, M., V. S. Shankar, O. A. Adebanjo, F. A. Lai, M. Pazianas, G. Sunavala, A. I. Spielman, and B. R. Rifkin. "Regulation of extracellular calcium sensing in rat osteoclasts by femtomolar calcitonin concentrations." American Journal of Physiology-Renal Physiology 271, no. 3 (September 1, 1996): F637—F644. http://dx.doi.org/10.1152/ajprenal.1996.271.3.f637.
Full textAbstract:
Certain eukaryotic cells can sense changes in their extracellular Ca2+ concentration through molecular structures termed Ca(2+)-sensing receptors (CaRs). We have shown recently that in the bone-resorbing osteoclast, a unique cell surface-expressed ryanodine receptor (RyR), functions as the CaR. The present study demonstrates that the sensitivity of this receptor is modulated by physiological femtomolar concentrations of the bone-conserving hormone, calcitonin. Calcitonin was found to inhibit cytosolic Ca2+ responses to both Ca2+ and Ni2+. The latter inhibition was mimicked by amylin (10(-12) M), calcitonin gene-related peptide (10(-12) M), cholera toxin (5 micrograms/l) and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) (2.5 x 10(-4) or 5 x 10(-4) M) and was reversed by the protein kinase A phosphorylation inhibitor, IP-20. Finally, using a quench flow module, we showed that cellular cAMP levels rise to a peak within 25 ms of calcitonin application; this is consistent with the peptide's rapid effect on CaR activation. We conclude, therefore, that cAMP plays a critical role in the control of CaR function by calcitonin.
37
Pozo-Rosich, P., RJ Storer, AR Charbit, and PJ Goadsby. "Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons." Cephalalgia 35, no. 14 (March 19, 2015): 1298–307. http://dx.doi.org/10.1177/0333102415576723.
Full textAbstract:
Background Calcitonin gene-related peptide (CGRP) receptor antagonism is an approach to migraine therapy. The locus of action of antimigraine treatment is not resolved. The objective was to investigate CGRP receptors in the ventrolateral periaqueductal gray (vlPAG) involved in the modulation of trigeminovascular nociception by descending influences on neurotransmission. Methods The presence of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), which form functional CGRP receptors, was investigated. CGRP and its receptor antagonists, olcegepant and CGRP ( 8 – 37 ), were microinjected into the vlPAG while changes of neural responses in the trigeminocervical complex (TCC) were monitored. Results Immunoreactivity indicated the presence of functional CGRP receptor components in the vlPAG and adjacent mesencephalic trigeminal nucleus. Inhibition of TCC responses to stimulation of dural afferents and ophthalmic cutaneous receptive fields after microinjection of bicuculline into vlPAG indicated a connection between the vlPAG and TCC neurons. CGRP facilitated these TCC responses, whereas olcegepant and CGRP ( 8 – 37 ) decreased them. Conclusions CGRP and its receptor antagonists act on neurons in the region of vlPAG to influence nociceptive transmission in the TCC. This suggests CGRP receptor antagonists may act at loci outside of the TCC and reinforces the concept of migraine as a disorder of the brain.
38
Schneider, H.-G., F. Raue, A. Koppold, W. Ruf, and R. Ziegler. "Homologous desensitization of calcitonin receptors and calcitonin-dependent adenylate cyclase in T47D cells." Acta Endocrinologica 128, no. 4 (April 1993): 373–78. http://dx.doi.org/10.1530/acta.0.1280373.
Full textAbstract:
Prolonged use of calcitonin (CT) in vivo leads to a loss of biological response (escape). To understand the molecular basis of this phenomenon, we examined desensitization of calcitonin receptors and down-regulation of adenylate cyclase response to CT in T47CD cells after a preincubation with CT. Preincubation with salmon or human CT (sCT, hCT) for 3 h led to a concentration-dependent loss of [125I]-sCT binding and a similar loss of adenylate cyclase response to a maximal stimulatory dose of sCT. At the same time there was an increased basal activity of the adenylate cyclase. After 24 h preincubation with sCT, basal cAMP levels fell considerably but not to basal levels. Time course experiments showed a delayed decline of maximally sCT-stimulated cAMP levels, which started after 1 h, while binding values declined over the first 60 min to one-third of the original values. Upon removal of CT from the medium, recovery of hormone binding occurred in parallel with the recovery of the adenylate cyclase response to sCT. T47D cells incubated with 25 μmol/l monensin, a lysosomal inhibitor, showed a persistent [125I]-sCT binding after removal of hormone, consistent with diminished intracellular receptor degradation. However, despite persistent binding to the cells, basal and stimulated cAMP levels dropped in the same manner as seen in controls. Our experiments support the view that tight binding of CT to its receptor stimulates adenylate cyclase in T47D cells, until receptors are removed by internalization. The physiological role of internalization of the CT receptor might be to end continuous stimulation of the adenylate cyclase, which occurs after binding.
39
Chai, Siew Yeen, George Christopoulos, Mark E. Cooper, and Patrick M. Sexton. "Characterization of binding sites for amylin, calcitonin, and CGRP in primate kidney." American Journal of Physiology-Renal Physiology 274, no. 1 (January 1, 1998): F51—F62. http://dx.doi.org/10.1152/ajprenal.1998.274.1.f51.
Full textAbstract:
Analysis of receptor distributions for125I-labeled amylin,125I-labeled calcitonin, and125I-labeled calcitonin gene-related peptide (CGRP) in Macaca fascicularis kidney by in vitro autoradiography revealed distinct patterns of binding for each peptide.125I-rat amylin bound primarily to the cortex, being associated with the distal tubule, including apparent binding to the juxtaglomerular apparatus.125I-salmon calcitonin displayed high-density binding in the cortex with low-density binding to the medulla. Emulsion autoradiography indicated that binding was associated with both distal tubule and thick ascending limb of the loop of Henle. Intense binding was also found often over juxtaglomerular apparatus.125I-rat CGRP-α exhibited low- to moderate-density binding to the inner medulla/papilla with high-density binding over small-, medium-, and large-caliber arteries. Weak binding to the glomerulus was also seen, but no binding was associated with cortical tubules. Competition binding studies, performed with each of the radioligands, revealed peptide specificity profiles for CGRP and calcitonin receptors that were similar to those described in rat. However, the monkey amylin receptors differed from those in rat, exhibiting relatively higher affinity for calcitonin peptides but reduced affinity for CGRP peptides. These studies suggest potential roles for amylin, calcitonin, and CGRP in primate renal function.
40
Schneider, H. G., F. Raue, A. Zink, A. Koppold, and R. Ziegler. "Down-regulation of calcitonin receptors in T47D cells by internalization of calcitonin-receptor complexes." Molecular and Cellular Endocrinology 58, no. 1 (July 1988): 9–15. http://dx.doi.org/10.1016/0303-7207(88)90048-2.
Full text
41
Warfvinge, Karin, and Lars Edvinsson. "Cellular distribution of PACAP-38 and PACAP receptors in the rat brain: Relation to migraine activated regions." Cephalalgia 40, no. 6 (December 6, 2019): 527–42. http://dx.doi.org/10.1177/0333102419893962.
Full textAbstract:
Background Pituitary adenylate cyclase-activating polypeptide (PACAP) occurs as either a 27- or 38-amino acid neuropeptide and belongs to the vasoactive intestinal polypeptide/glucagon/secretin family of peptides. PACAP and vasoactive intestinal polypeptide have a 68% homology of their amino acid sequences and share three B-type G-protein coupled receptors: VPAC1, VPAC2 and PAC1 receptors. Methods/results The distribution of PACAP-38 and its receptors in the brain is only partly described in the literature. Here, we have performed a study to provide the more general picture of this system in rat brain in order to understand a putative role in primary headaches and partly in relation to the calcitonin gene-related peptide system. We observed a rich expression of PACAP-38 and PAC1 receptor immunoreactivity in many regions throughout the cerebrum, cerebellum and brainstem. The expression pattern points to multiple functions, not least associated with pain and reactions to pain. The expression of VPAC1 and VPAC2 receptor immunoreactivity was very sparse. In several regions such as the cerebral cortex, trigeminal nucleus caudalis, hypothalamus and pons there was a close relation to calcitonin gene-related peptide expression. Conclusion The findings suggest that the rich supply of PACAP-38 and PAC1 receptors is associated with basic functional responses in the central nervous system (CNS), and there are important close anatomical relations with calcitonin gene-related peptide in CNS regions associated with migraine pathophysiology.
42
Fischer, J. A., W. Born, and R. Muff. "Calcitonin Gene-Related Peptide (Cgrp), Adrenomedullin (Am), Amylin, And Calcitonin (Ct) Receptors And Overlapping Biological Actions." Scientific World JOURNAL 1 (2001): 4. http://dx.doi.org/10.1100/tsw.2001.413.
Full textAbstract:
CGRP, AM, amylin, and CT have in common N-terminal 6-7 amino acid ring structures linked by disulfide bridges and amidated C-termini required for biological activity. For the related bioactive peptides, receptor-binding sites linked to cAMP stimulation and to a lesser extent to the phospholipase C signaling pathway have been identified in tissue specific manner. The highest density of CGRP receptors has been recognized in the cerebellum and the spinal cord. There photoaffinity-labeled N-glycosylated 60,000 and 54,000 Mr proteins are converted to 46,000 and 41,000 Mr components following endoglycosidase F/N-glycosidase F treatment. The same proteins were specifically labeled with [125I]-hCGRP-I(1-37) and -(8-37). Some cross-reaction between the CGRP receptor and AM was evident whereas amylin and CT were only recognized at over 10-7 M. A different AM receptor localized predominantly in the lung recognized CGRP at low, and amylin and calcitonin at equally high concentrations. CT receptor binding sites have been identified in osteoclasts and in the periventricular region of the brain. They cross-reacted with amylin at low concentrations and with CGRP and AM at over 10-7 M. Amylin receptor binding sites cross-reacting with salmon CT and CGRP but not with hCT and adrenomedullin to any great extent were originally described by Sexton in the nucleus accumbens and may represent a second CGRP receptor. The structure of a CT receptor was elucidated by the group of Goldring in 1991 through molecular cloning, and of a 60% homologous human CT receptor-like receptor (CRLR) shortly thereafter here. The latter was an orphan receptor until the discovery of the receptor-activity-modifying proteins (RAMP) by Foord which upon coexpression yield a CGRP receptor with RAMP1 and an AM receptor with RAMP2. Coexpression of the hCT receptor isotype 2 revealed a CGRP/amylin receptor with RAMP1 and an amylin receptor isotype with RAMP3. The CRLR/RAMP1 receptor antagonized by CGRP(8-37) corresponds to the CGRP1 receptor defined by Quirion, whereas his CGRP2 receptor remains to be identified. Another CGRP receptor isotype remains to be discovered in the cerebellum with no detectable CRLR encoding mRNA. Overlapping biological actions include inhibition of bone resorption obtained predominantly with CT, but also at high concentrations with CGRP, AM, and amylin. CGRP and AM are potent vasodilators, an effect shared with CT at pharmacological concentrations. Biological actions of amylin include suppression of insulin secretion, stimulation of glycogenolysis and inhibition of glycogen synthesis. In conclusion, the hCT2 receptor or the CRLR are associated with one of three RAMPs to bind to CGRP, AM, or amylin.
43
Naduchamy, Krishna P., and Varadarajan Parthasarathy. "A Review of the Potential Receptors of Migraine with a Special Emphasis on CGRP to Develop an Ideal Antimigraine Drug." Current Molecular Pharmacology 14, no. 1 (December 31, 2020): 11–26. http://dx.doi.org/10.2174/1874467213999200824124532.
Full textAbstract:
Background and Objective: Migraine is a neurovascular syndrome associated with unilateral, throbbing headache accompanied with nausea, vomiting and photo/phonophobia. Several proteins are involved in the etiopathogenesis of migraine headache. The aim of the present review is to give an insight into the various target proteins involved in migraine headache pertaining to the development of a potential anti-migraine drug molecule. Proteins/receptors such as serotonin (5-HT), Calcitonin Gene Related Peptide (CGRP), Transient Receptor Potential Vanilloid (TRPV1), cannabinoid, glutamate, opioid and histamine receptors play various roles in migraine. The nature of the proteins, their types, binding partner membrane proteins and the consequences of the reactions produced have been discussed. The studies conducted on animals and humans with the above mentioned target proteins/receptors and the results obtained have also been reviewed. Conclusion: Calcitonin Gene Related Peptide (CGRP), a G protein coupled receptor (GPCR) significantly contributed to the progression of migraine. CGRP antagonist inhibits the release of CGRP from trigeminal neurons of trigeminal ganglion. Based on the study results, the present review suggests that the inhibition of CGRP receptor might be a successful way to treat migraine headache. Currently, researchers across the world are focussing their attention towards the development of novel molecules to treat migraine headache by targeting CGRP receptor which can be attributed to its specificity among the several proteins involved in migraine.
44
LEUTHÄUSER, Kerstin, Remo GUJER, Amaya ALDECOA, R. ANNE McKINNEY, Roman MUFF, Jan A. FISCHER, and Walter BORN. "Receptor-activity-modifying protein 1 forms heterodimers with two G-protein-coupled receptors to define ligand recognition." Biochemical Journal 351, no. 2 (October 10, 2000): 347–51. http://dx.doi.org/10.1042/bj3510347.
Full textAbstract:
Receptor-activity-modifying proteins (RAMPs) with single transmembrane domains define the function of two G-protein-coupled receptors of the B family. Cell-surface complexes of human RAMP1 (hRAMP1) and human calcitonin (CT) receptor isotype 2 (hCTR2) or rat CT-receptor-like receptor (rCRLR) have now been identified through protein cross-linking, co-immunoprecipitation and confocal microscopy. They are two distinct CT-gene-related peptide (CGRP) receptors coupled to cAMP production and pharmacologically distinguished by the CT and CGRP antagonists salmon CT(8-32) and human or rat CGRP(8-37). Thus direct molecular interactions of hRAMP1 with hCTR2 or rCRLR are required for CGRP recognition. hCTR2, moreover, adopts non-traditional functions through its association with hRAMP1.
45
Nussenzveig, Daniel R., Maria De Fatima C. Matos, and Colette N. Thaw. "Human calcitonin receptor is directly targeted to and retained in the basolateral surface of MDCK cells." American Journal of Physiology-Cell Physiology 275, no. 5 (November 1, 1998): C1264—C1276. http://dx.doi.org/10.1152/ajpcell.1998.275.5.c1264.
Full textAbstract:
The human calcitonin receptor (hCTR) is expressed in polarized cells of the kidney, bone, and nervous system. In the kidney, hCTRs are found in cells of the distal nephron to which blood-borne calcitonin has access only at the basolateral surface. We expressed hCTR subtypes 1 and 2 in Madin-Darby canine kidney (MDCK) cells to establish a cell model useful for delineating the molecular mechanisms underlying hCTR polarity. Selective cell surface incubation demonstrated functional polarity of hCTRs by equilibrium binding or cross-linking of radioiodinated salmon calcitonin (125I-sCT) and cAMP accumulation stimulated by sCT. We estimated that at the steady state there are 40-fold more hCTRs on the basolateral than on the apical side. Domain-selective cell surface biotinylation followed by immunoblotting of streptavidin-agarose-fractionated biotinylated glycoproteins independently confirmed the polarized distribution of FLAG epitope-tagged hCTR-2 in the basolateral domain. Confocal microscopy of immunostained receptors revealed that hCTRs are concentrated on a lateral subdomain of the basolateral membrane. Cell surface arrival assay of newly formed receptors demonstrated that direct delivery to the basolateral domain is the mechanism by which hCTRs become polarized. Measurement of receptor turnover on the basolateral surface showed that retention contributes to hCTR distribution at the steady state.
46
Kuwasako, Kenji, Kazuo Kitamura, Yasuko Nagoshi, and Tanenao Eto. "Novel calcitonin-(8–32)-sensitive adrenomedullin receptors derived from co-expression of calcitonin receptor with receptor activity-modifying proteins." Biochemical and Biophysical Research Communications 301, no. 2 (February 2003): 460–64. http://dx.doi.org/10.1016/s0006-291x(02)03072-3.
Full text
47
Russell, F. A., R. King, S. J. Smillie, X. Kodji, and S. D. Brain. "Calcitonin Gene-Related Peptide: Physiology and Pathophysiology." Physiological Reviews 94, no. 4 (October 2014): 1099–142. http://dx.doi.org/10.1152/physrev.00034.2013.
Full textAbstract:
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.
48
Cardoso, J. C. R., M. S. Clark, F. A. Viera, P. D. Bridge, A. Gilles, and D. M. Power. "The secretin G-protein-coupled receptor family: teleost receptors." Journal of Molecular Endocrinology 34, no. 3 (June 2005): 753–65. http://dx.doi.org/10.1677/jme.1.01730.
Full textAbstract:
Twenty-one members of the secretin family (family 2) of G-protein-coupled receptors (GPCRs) were identified via directed cloning and data-mining of the Fugu Genome Consortium database, representing the most comprehensive description of secretin GPCRs in a teleost fish to date. Duplicated genes were identified for many of the family members, namely the receptors for pituitary adenylate cyclase-activating polypeptide (PACAP)/vasoactive intestinal peptide (VIP), calcitonin, calcitonin gene-related peptide (CGRP), growth hormone releasing hormone (GHRH), glucagon receptor/glucagon-like peptide (GLP) and parathyroid hormone-related peptide (PTHrP)/PTH. Mining of other teleost genomes (zebrafish and Tetraodon) revealed that the duplicated genes identified in the Takifugu genome were also present in these fish. Additional database searching of the Escherichia coli, yeast, Drosophila, Caenorhabditis elegans and Ciona genomes revealed that the family 2 of GPCRs were only present in the multicellular organisms. Orthologues of all the human secretin receptors were identified with the exception of secretin itself. Additional database searches in the Fugu Genome Consortium database also failed to reveal a secretin ligand and so it is hypothesised that both the receptor and the ligand evolved after the divergence of teleost/tetrapod lineages. Phylogenetic analysis at both the protein and the DNA level provided strong support for each of the individual receptor family groupings, but weak support between groups, making evolutionary inferences difficult. A more critical analysis of the PACAP/VIP receptor family confirmed previous hypotheses that the vasoactive intestinal peptide receptor (VPAC1R) gene is the ancestral form of the receptor.
49
Grossini, Elena, Claudio Molinari, David A. S. G. Mary, Francesca Uberti, Philippe Primo Caimmi, and Giovanni Vacca. "Intracoronary intermedin 1–47 augments cardiac perfusion and function in anesthetized pigs: role of calcitonin receptors and β-adrenoreceptor-mediated nitric oxide release." Journal of Applied Physiology 107, no. 4 (October 2009): 1037–50. http://dx.doi.org/10.1152/japplphysiol.00569.2009.
Full textAbstract:
Systemic intermedin (IMD)1–47 administration has been reported to result in vasodilation and marked hypotension through calcitonin-related receptor complexes. However, its effects on the coronary circulation and the heart have not been examined in vivo. The present study was therefore planned to determine the primary in vivo effect of IMD1–47 on coronary blood flow and cardiac function and the involvement of the autonomic nervous system and nitric oxide (NO). In 35 anesthetized pigs, IMD1–47, infused into the left anterior descending coronary artery at doses of 87.2 pmol/min, at constant heart rate and arterial blood pressure, augmented coronary blood flow and cardiac function. These responses were graded in a further five pigs by increasing the infused dose of IMD1–47 between 0.81 and 204.1 pmol/min. In the 35 pigs, the blockade of cholinergic receptors (intravenous atropine, 5 pigs), α-adrenoceptors (intravenous phentolamine, 5 pigs), and β1-adrenoceptors (intravenous atenolol, 5 pigs) did not abolish the cardiac response to IMD1–47, the effects of which were prevented by blockade of β2-adrenoceptors (intravenous butoxamine, 5 pigs), NO synthase (intracoronary Nω-nitro-l-arginine methyl ester, 5 pigs), and calcitonin-related receptors (intracoronary CGRP8–37/AM22–52, 10 pigs). In porcine coronary endothelial cells, IMD1–47 induced the phosphorylation of endothelial NO synthase and NO production through cAMP signaling leading to ERK, Akt, and p38 activation, which was prevented by the inhibition of β2-adrenoceptors, calcitonin-related receptor complexes, and K+ channels. In conclusion, IMD1–47 primarily augmented coronary blood flow and cardiac function through the involvement of calcitonin-related receptor complexes and β2-adrenoreceptor-mediated NO release. The intracellular signaling involved cAMP-dependent activation of kinases and the opening of K+ channels.
50
Zaidi, M., T. J. Chambers, R. E. Gaines Das, H. R. Morris, and I. MacIntyre. "A direct action of human calcitonin gene-related peptide on isolated osteoclasts." Journal of Endocrinology 115, no. 3 (December 1987): 511–18. http://dx.doi.org/10.1677/joe.0.1150511.
Full textAbstract:
ABSTRACT The calcitonin gene encodes a small family of peptides: calcitonin, calcitonin gene-related peptide (CGRP) and katacalcin. Whereas calcitonin is concerned with skeletal maintenance, the function, if any, of katacalcin is still unknown. In the present study we have assessed resorption of human cortical bone substrate by isolated rat osteoclasts and have shown that CGRP acts directly on the osteoclast to inhibit bone resorption. The three CGRP peptides (rat, human(a) and human(β)) caused an almost equivalent decrease in osteoclastic bone resorption and were approximately 1000-fold less potent than human calcitonin in this respect. The responses of human calcitonin and human CGRP(α) were additive. Furthermore, prior treatment with trypsin to destroy receptors abolished the responsiveness of osteoclasts to CGRP and calcitonin. The carboxyl- and amino-terminal fragments of CGRP were found not to inhibit bone resorption, suggesting that the whole molecule of CGRP is necessary for biological activity. We have therefore suggested that the calcitonin-like effects of CGRP, seen both in vivo in the rat bioassay and in vitro in organ cultures, are due to the direct action of CGRP on the osteoclast, probably mediated through the calcitonin receptor. Though it is unlikely that CGRP is involved in the regulation of plasma calcium, the peptide may be an important local regulator of bone cell function. J. Endocr. (1987) 115,511–518