The role of the CGRP-receptor component protein (RCP) in adrenomedullin receptor signal transduction.
G protein-coupled receptors are usually thought to act as monomer receptors that bind ligand and then interact with G proteins to initiate signal transduction. In this study we report an intracellular peripheral membrane protein named the calcitonin gene-related peptide (CGRP)-receptor component protein (RCP) required for signal transduction at the G protein-coupled receptor for adrenomedullin. Cell lines were made that expressed an antisense construct of the RCP cDNA, and in these cells diminished RCP expression correlated with loss of adrenomedullin signal transduction. In contrast, loss of RCP did not diminish receptor density or affinity, therefore RCP does not appear to act as a chaperone protein. Instead, RCP represents a novel class of protein required to couple the adrenomedullin receptor to the cellular signal transduction pathway. A candidate adrenomedullin receptor named the calcitonin receptor-like receptor (CRLR) has been described, which forms high affinity adrenomedullin receptors when co-expressed with the accessory protein receptor-activity modifying protein 2 (RAMP2). RCP co-immunoprecipitated with CRLR and RAMP2, indicating that a functional adrenomedullin receptor is composed of at least three proteins: the ligand binding protein (CRLR), an accessory protein (RAMP2), and a coupling protein for signal transduction (RCP).
Prado
M A
MA
Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, FL 33101, USA.
Evans-Bain
B
B
Oliver
K R
KR
Dickerson
I M
IM
D016475:3T3 Cells; D053607:Adrenomedullin; D000595:Amino Acid Sequence; D000818:Animals; D058286:Calcitonin Receptor-Like Protein; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006168:Guinea Pigs; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009865:Oocytes; D010455:Peptides / Q000378:metabolism; D011233:Precipitin Tests; D016372:RNA, Antisense / Q000494:pharmacology; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin / Q000276:immunology / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018000:Receptors, Peptide / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D014982:Xenopus laevis
D058286:Calcitonin Receptor-Like Protein; C545579:Calcrl protein, mouse; C491563:Crcp protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010455:Peptides; D016372:RNA, Antisense; C545506:Ramp2 protein, mouse; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D018015:Receptors, Calcitonin Gene-Related Peptide; D018000:Receptors, Peptide; D053607:Adrenomedullin