No abstract

The calcitonin (CT) receptor (CTR) was cloned by Goldring in 1991. For all the other receptors of the CT family of hormones and neuropeptidcs receptor-activity-modifying proteins (RAMP) arc required for ligand recognition. Thus a new principle for the functional expression of G protein-coupled receptors has been discovered by Foord in 1998. The initially orphan CT receptor-like receptor (CRLR) was identified as a calcitonin gene-related peptidc (CGRP) receptor when co-expressed with RAMPI. The same receptor is specific for adrenomedullin (AM) in the presence of RAMP2. I n the absence of RAMP the C T R with 60% homology to the CRLR predominantly recognizes CT. An amylin/CGRP receptor is revealed when the C T R is co-expressed with RAMPI. Together with RAMP3 the C T R interacts with amylin alone. Two C G R P receptor isotypes, the CRLRIRAMPI antagonized by CGRP(8-37) and not by salmon CT(8-32), and the CTR/RAMPl amagonized by salmon CT(8-32) can be differentiated. Thus noncovalent association of two class I1 G protein-coupled receptors with three RAMP results in heterodimeric RAMP/receptor complexes essential for the recognition of CGRP, AM or amylin at the cell surface.c11 Receptor component protein (rcp): a member of a multiprotein complex required for G protein-coupled signal transductionThe calcitonin gene-related peptide (CGRP)-receptor component protein (RCP) is a 17 kDa intracellular peripheral membrane protein required for signal transduction at the G protein-couplcd receptor calcitonin receptor-like receptor (CRLR). CRLR functions as a C G R P receptor when co-expressed with an accessory protein named receptor activity modifying protein-1 (RAMPI), and as an adrenomedullin receptor when co-expressed with RAMP2. When RCP was depleted from NIH3T3 cells using antisense strategy, loss of R C P protein correlated with dccrcased CAMP production by C G R P or adrenomedullin in the antisense cells. In contrast, loss of R C P had n o effect o n ligand binding. Therefore, R C P is not acting as a chaperone for CRLR; instead RCP couples CRLR to the cellular signal transduction machinery. RCP co-immunoprecipitates with CRLR, RAMPI, and RAMP2 from NIH3T3 cells. This suggests that a functional C G R P or adrenomedullin receptor is a trimer of proteins: a ligand binding protein (CRLR), an accessory protein that determines pharmacologic specificity (RAMPI or RAMPZ), and a protein that couples the receptor to the cellular signal transduction pathway (RCP).The calcium independent receptors for latrotoxin (CIRLI -3) constitute a family of seven transmembrane receptors with an unsually large N-terminal, extracellular domain which comprises several motifs usually found in cell adhesion molecules. By yeast two hybrid screening, we have identified the intracellular Cterminus of CIRLl and CIRL2 as interaction partners of the PDZ domain of the ProSAP/SSTRIP family of postsynaptic proteins (SSTRIP, ProSAPl and 2, also known as shankl-3). Overlay assays indicate that especially the ProSAPl PDZ domain interacts strongly with the C-...