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 in teracting with G-proteins do not function as monomers, but often require ac cessory proteins for function. Some of these accessory proteins are chapero nes, required for correct transport of the receptor to the cell surface, bu t the function of many accessory proteins remains unknown, We determined th e role of an accessory protein for the receptor for calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide. me have previously show n that this accessory protein, the CGRP-receptor component protein (RCP), i s expressed in CGRP responsive tissues and that RCP protein expression corr elates 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 tr ansduction were greatly reduced, However, the loss of RCP did not effect CG RP binding or receptor density, indicating that RCP did not behave as a cha perone but was instead coupling the CGRP receptor to downstream effecters. A candidate CGRP receptor named calcitonin receptor-like receptor (CRLR) ha s been identified, and in this study RCP co-immunoprecipitated with CRLR in dicating that these two proteins interact directly. Since CGRP and adrenome dullin can both signal through CRLR, which has been previously shown to req uire a chaperone protein for function, we now propose that a functional CGR P or adrenomedullin receptor consists of at least three proteins: the recep tor (CRLR), the chaperone protein (RAMP), and RCP that couples the receptor to the cellular signal transduction pathway.