Understanding amylin Receptors

Amylin is a 37 amino acid peptide that is co-secreted with insulin from pancreatic β-cells following nutrient ingestion, acting to inhibit gastric emptying, feeding and insulin-stimulated glycogen synthesis. Amylin is a member of the calcitonin (CT) family of peptides, which include CT, CT gene-related peptides (CGRP) and adrenomedullin (AM). The receptors for these peptides comprise the CT receptor (CTR) and the CTR-like receptor (CLR) that may be complexed with one of three receptor activity modifying proteins (RAMPs). Amylin receptors are formed when the CTR is in complex with RAMP1, RAMP2 or RAMP3, forming AMY₁, AMY₂ and AMY₃ receptors, respectively. Each of these receptors, while binding amylin with similar affinity, has a distinct agonist and antagonist pharmacology. Analysis of RAMP chimeras and deletion constructs has provided insight into domains of RAMPs that contribute to ligand and signaling specificity. The N-terminal domain is the principle domain involved in alteration of ligand binding specificity, while the C-terminal domain contributes to the peptide signaling profile of the receptor complexes and could be directly involved in the interaction with G proteins.