Abstract
Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse biological effects including potent vasodilator activity. We report here the cloning of a complementary DNA (cDNA) encoding a human CGRP1 receptor, which shares significant peptide sequence homology with the human calcitonin receptor, a member of the G-protein-coupled receptor superfamily. Northern blot analysis revealed that the messenger RNA for this receptor is predominantly expressed in the lung and heart. In situ studies showed specific localization of the receptor mRNA to alveolar cells in the lung and to cardiac myocytes in the heart. Stable expression of the cDNA in human embryonic kidney 293 (HEK 293) cells produced specific, high affinity binding sites for CGRP that displayed pharmacological and functional properties very similar to native human CGRP1 receptor. Exposure of these cells to CGRP resulted in a 60-fold increase in cAMP production, which was inhibited in a competitive manner by the CGRP1 receptor antagonist, CGRP-(8-37).
Highlights
Calcitonin gene-related peptide (CGRP)1 is 37-amino acid peptide that exists as highly homologous ␣ or  isoforms in both human and rat [1, 2]. ␣- and -CGRP display very similar biological activities, including peripheral and cerebral vasodilation [3], cardiac acceleration [4], regulation of calcium metabolism [5], reduction of intestinal motility [6], regulation of glucose metabolism [7], diminution of appetite [8], and reduction of growth hormone release [9]
We hypothesized that the CGRP and recently cloned calcitonin (CT) receptors might display close homology since (i) like the G-protein-coupled CT receptor [26], CGRP signaling appears to be mediated through the activation of adenylyl cyclase, (ii) at high concentrations CT interacts with the CGRP binding site [27], and (iii) CGRP and CT share the same mRNA transcript and are produced through alternate splicing [1], as are the substance P/K ligands that cross-interact with tachykinin receptors [28]
When expressed sequence tag (EST) analysis [15,16,17] of complementary DNA (cDNA) clones derived from a human synovial tissue cDNA library identified a clone demonstrating significant homology to the human CT receptor, this cDNA was selected for further evaluation
Summary
Calcitonin gene-related peptide (CGRP)1 is 37-amino acid peptide that exists as highly homologous ␣ or  isoforms in both human and rat [1, 2]. ␣- and -CGRP display very similar biological activities, including peripheral and cerebral vasodilation [3], cardiac acceleration [4], regulation of calcium metabolism [5], reduction of intestinal motility [6], regulation of glucose metabolism (reduction of insulin secretion and insulin sensitivity) [7], diminution of appetite [8], and reduction of growth hormone release [9]. We report here the cloning of a complementary DNA (cDNA) encoding a human CGRP1 receptor, which shares significant peptide sequence homology with the human calcitonin receptor, a member of the G-protein-coupled receptor superfamily.
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