Academic literature on the topic 'Heptahelical receptors'

Chemoattractants, including chemokines such as interleukin 8 (IL-8) and related proteins, activate leucocytes via seven-transmembrane-domain G-protein-coupled receptors. A cDNA for a novel receptor of this kind consisting of 327 amino acids was isolated from a human blood monocyte cDNA library. The polypeptide, termed monocyte-derived receptor 15 (MDR15), is an alternative form of the Burkitt's lymphoma receptor 1 (BLR1) encoded by a human Burkitt's lymphoma cDNA [Dobner, Wolf, Emrich and Lipp (1992) Eur. J. Immunol. 22, 2795-2799]. MDR15 and BLR1 cDNAs differ in the 5′ region, where the open reading frame of MDR15 is shorter by 45 codons. Southern-blot analysis indicates that the two transcripts for MDR15 and BLR1 are encoded by the same gene. Northern-blot analysis using a probe that hybridizes with both mRNAs demonstrated high-level expression in chronic B-lymphoid leukaemia and non-Hodgkin's lymphoma cells and, to a lesser extent, peripheral blood monocytes and lymphocytes. Reverse transcription-PCR studies with MDR15- and BLR1-specific primers showed similar levels of transcripts for both receptors in RNA that was positive in Northern-blot analysis. MDR15 and BLR1 have high structural similarity to receptors for human IL-8 (about 40% amino acid identity) and other chemokines. However, none of a series of radiolabelled chemokines (IL-8, NAP-2, GRO alpha, PF4, IP10, MCP-1, MCP-2, MCP-3, I-309, RANTES and MIP-1 alpha) and other ligands (C3a and leukotriene B4) bound to Jurkat transfectants that stably expressed either MDR15 or BLR1 mRNA. The fact that MDR15 and BLR1 are expressed on leucocytes and show marked sequence similarity to chemokine receptors suggests the existence of as yet unidentified chemokines. Alternative transcript formation affecting the 5′-terminal part of the coding region may be a way to modify ligand-binding selectivity.

Chemokine signaling is essential for coordinated cell migration in health and disease to specifically govern cell positioning in space and time. Typically, chemokines signal through heptahelical, G protein-coupled receptors to orchestrate cell migration. Notably, chemokine receptors are highly dynamic structures and signaling efficiency largely depends on the discrete contact with the ligand. Promiscuity of both chemokines and chemokine receptors, combined with biased signaling and allosteric modulation of receptor activation, guarantees a tightly controlled recruitment and positioning of individual cells within the local environment at a given time. Here, we discuss recent insights in understanding chemokine gradient formation by atypical chemokine receptors and how typical chemokine receptors can transmit distinct signals to translate guidance cues into coordinated cell locomotion in space and time.

Background Some anesthetics relax airway smooth muscle in part by inhibiting acetylcholine-induced increases in Ca2+ sensitivity, an effect associated with inhibition of guanosine nucleotide exchange at the alpha subunit of the Gq/11 (Galphaq/11) heterotrimeric G protein. This study tested the hypothesis that these anesthetic effects are not unique to the muscarinic receptor but are a general property of the heptahelical receptors that increase Ca2+ sensitivity in airway smooth muscle. Methods Anesthetic effects on agonist-induced increases in Ca2+ sensitivity were measured in porcine airway smooth muscle strips permeabilized with S. aureus alpha-toxin. Anesthetic effects on basal (without agonist stimulation) and agonist-promoted Galphaq/11 guanosine nucleotide exchange were determined in crude membranes prepared from porcine airway smooth muscle. The nonhydrolyzable, radioactive form of guanosine 5'-triphosphate was used as the reporter for nucleotide exchange at Galphaq/11. Results Acetylcholine, endothelin-1, and histamine caused a concentration-dependent increase in Ca2+ sensitivity. Halothane (0.67 +/- 0.07 mM) and hexanol (10 mM) significantly inhibited the increase in Ca2+ sensitivity induced by each agonist. Each agonist also caused a time- and concentration-dependent increase in Galphaq/11 nucleotide exchange. Neither anesthetic had an effect on basal Galphaq/11 nucleotide exchange, whereas halothane and hexanol significantly inhibited the increase in Galphaq/11 nucleotide exchange promoted by each agonist. Conclusion These data suggest that inhibition of agonist-promoted guanosine nucleotide exchange at Galphaq/11 by some anesthetics may be a general property of heptahelical receptors involved cellular processes mediated by Galphaq/11, including muscarinic, endothelin-1, and histamine receptor activation of Ca2+ sensitivity.