CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors.
It is becoming clear that receptors that initiate signal transduction by interacting with G-proteins do not function as monomers, but often require accessory proteins for function. Some of these accessory proteins are chaperones, required for correct transport of the receptor to the cell surface, but the function of many accessory proteins remains unknown. We determined the role of an accessory protein for the receptor for calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide. We have previously shown that this accessory protein, the CGRP-receptor component protein (RCP), is expressed in CGRP responsive tissues and that RCP protein expression correlates with the biological efficacy of CGRP in vivo. However, the function of RCP has remained elusive. In this study stable cell lines were made that express antisense RCP RNA, and CGRP- and adrenomedullin-mediated signal transduction were greatly reduced. However, the loss of RCP did not effect CGRP binding or receptor density, indicating that RCP did not behave as a chaperone but was instead coupling the CGRP receptor to downstream effectors. A candidate CGRP receptor named calcitonin receptor-like receptor (CRLR) has been identified, and in this study RCP co-immunoprecipitated with CRLR indicating that these two proteins interact directly. Since CGRP and adrenomedullin can both signal through CRLR, which has been previously shown to require a chaperone protein for function, we now propose that a functional CGRP or adrenomedullin receptor consists of at least three proteins: the receptor (CRLR), the chaperone protein (RAMP), and RCP that couples the receptor to the cellular signal transduction pathway.
Evans
B N
BN
Departments of Physiology and Biophysics, Biochemistry and Molecular Biology, and Neuroscience Program, University of Miami School of Medicine, Miami, Florida 33101, USA.
Rosenblatt
M I
MI
Mnayer
L O
LO
Oliver
K R
KR
Dickerson
I M
IM
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D009479:Neuropeptides / Q000737:chemistry; D011233:Precipitin Tests; D016372:RNA, Antisense / Q000378:metabolism; D058265:Receptors, Adrenomedullin; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D018000:Receptors, Peptide / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction; D014665:Vasodilator Agents / Q000737:chemistry
C491563:Crcp protein, mouse; D018076:DNA, Complementary; D003902:Detergents; D009479:Neuropeptides; D016372:RNA, Antisense; D058265:Receptors, Adrenomedullin; D018015:Receptors, Calcitonin Gene-Related Peptide; D018000:Receptors, Peptide; D014665:Vasodilator Agents; D010450:Endopeptidases; D019204:GTP-Binding Proteins