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Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor function
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Barwell, James, Conner, Alex C. and Poyner, David R. (2011) Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor function. Biochimica et Biophysica Acta - Molecular Cell Research, Vol.1813 (No.10). pp. 1906-1916. doi:10.1016/j.bbamcr.2011.06.005
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Official URL: http://dx.doi.org/10.1016/j.bbamcr.2011.06.005
Abstract
The first and third extracellular loops (ECL) of G protein-coupled receptors (GPCRs) have been implicated in ligand binding and receptor function. This study describes the results of an alanine/leucine scan of ECLs 1 and 3 and loop-associated transmembrane (TM) domains of the secretin-like GPCR calcitonin receptor-like receptor which associates with receptor activity modifying protein 1 to form the CGRP receptor. Leu195Ala, Val198Ala and Ala199Leu at the top of TM2 all reduced alpha CGRP-mediated cAMP production and internalization: Leu195Ala and Ala199Leu also reduced alpha CGRP binding. These residues form a hydrophobic cluster within an area defined as the "minor groove" of rhodopsin-like GPCRs. Within ECL1, Ala203Leu and Ala206Leu influenced the ability of alpha CGRP to stimulate adenylate cyclase. In TM3, His219Ala, Leu220Ala and Leu222Ala have influences on alpha CGRP binding and cAMP production; they are likely to indirectly influence the binding site for alpha CGRP as well as having an involvement in signal transduction. On the exofacial surfaces of TMs 6 and 7, a number of residues were identified that reduced cell surface receptor expression, most noticeably Leu351Ala and Glu357Ala in TM6. The residues may contribute to the RAMP1 binding interface. Ile360Ala impaired alpha CGRP-mediated cAMP production. Ile360 is predicted to be located close to ECL2 and may facilitate receptor activation. Identification of several crucial functional loci gives further insight into the activation mechanism of this complex receptor system and may aid rational drug design.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QP Physiology Q Science > QR Microbiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||
| Library of Congress Subject Headings (LCSH): | G proteins -- Receptors, Radioligand assay, Ligand binding (Biochemistry), Cellular signal transduction | ||||
| Journal or Publication Title: | Biochimica et Biophysica Acta - Molecular Cell Research | ||||
| Publisher: | Elsevier Science BV | ||||
| ISSN: | 0167-4889 | ||||
| Official Date: | October 2011 | ||||
| Dates: |
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| Volume: | Vol.1813 | ||||
| Number: | No.10 | ||||
| Number of Pages: | 11 | ||||
| Page Range: | pp. 1906-1916 | ||||
| DOI: | 10.1016/j.bbamcr.2011.06.005 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | British Heart Foundation | ||||
| Grant number: | FS/05/054 (BHF) |
Data sourced from Thomson Reuters' Web of Knowledge
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