It is well known that the action of glucose on pancreatic islets results in increased plasma insulin levels. Nevertheless, high blood glucose levels are not solely responsible for increased insulin secretion (for review, see Ref. 1). For example, in 1964 McIntyre et al. (2) demonstrated that intravenous injection of glucose resulted in a smaller insulin release than that resulting from intrajejunal glucose injection, even though the latter produced lower blood glucose levels compared with the former. Hence, glucose-dependent insulin secretion requires a nutrientdependent component, which was believed to be an endocrine transmitter termed an "incretin" (3). It has since been demonstrated that two hormones, glucagon-like peptide-1 and glucosedependent insulinotropic polypeptide, are responsible for the incretin effect (1).The predominant active form of GLP-1 is actually glucagonlike peptide-1(7-36)amide (termed GLP-1 1 throughout this paper), a 30-residue peptide hormone derived from the post-translational modification of proglucagon in intestinal L cells (1). GLP-1 not only increases glucose-dependent insulin secretion (4 -6), but it also decreases glucose-dependent glucagon secretion (7, 8) and decelerates gastric emptying (9). In addition, GLP-1 has been shown to reduce appetite in rats (10) and to stimulate proinsulin gene transcription and biosynthesis in pancreatic ␤-cells (11, 12). The physiological roles of GLP-1 in maintaining blood sugar levels, via a glucose-dependent mechanism, have heightened interest in the GLP-1 receptor (GLP-1R) as a target for glucose-dependent therapeutic agents designed to treat hyperglycemia resulting from diabetes (13,14). Unfortunately, the half-life of GLP-1 itself after subcutaneous injection is very short because of dipeptidyl peptidase IV cleavage of the first 2 N-terminal residues (15), and so future research requires the design of physiologically stable GLP-1R agonists.The venom of the Gila monster Heloderma suspectum contains a mixture of compounds that includes several peptides related in sequence to GLP-1. Two of these, exendin-3 and exendin-4, are 39-amino acid peptides that share ϳ50% sequence identity to GLP-1 itself and are indeed potent GLP-1R agonists (Fig. 1) (16, 17). Interestingly, although GLP-1 affinity is highly sensitive to N-terminal cleavage, exendin-4 can be truncated by up to 8 residues at its N terminus without significant loss of affinity, suggesting that relative to GLP-1, the central and/or C-terminal residues form additional stabilizing contacts with the receptor (15, 18). Nevertheless, the first two amino acids are also essential for the efficacy of exendin peptides because, once removed, the truncated exendin peptides function as antagonists or inverse agonists (16 -19).

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-...