CRLR

CRLR, short for calcitonin receptor-like receptor, is a G protein-coupled receptor (GPCR) of the class B1 family. In humans it is encoded by the CALCRL gene. Unlike some receptors, CRLR lacks high affinity for calcitonin by itself, and its ligand specificity is determined by receptor activity-modifying proteins (RAMPs).

When CRLR associates with RAMP1, the complex functions as the CGRP receptor, binding calcitonin gene-related peptide. Association with RAMP2 or RAMP3 forms two adrenomedullin receptors: AM1 (CRLR+RAMP2) and AM2 (CRLR+RAMP3). The CRLR-RAMP complexes can also respond to related peptides such as intermedin (adrenomedullin 2).

CRLR is expressed in a variety of tissues, including the brain and vascular endothelium, as well as smooth muscle and other organs. Signaling through CRLR-RAMP complexes is primarily via Gs proteins, leading to increased intracellular cyclic AMP and activation of downstream pathways that regulate vascular tone, permeability, angiogenesis, and neuroendocrine functions.

Clinical and research significance is linked to CGRP signaling and migraine. The CRLR-containing CGRP receptor is a target for migraine therapies, including CGRP receptor antagonists and monoclonal antibodies that reduce migraine frequency. Beyond migraine, CRLR signaling and its adrenomedullin receptors are studied in cardiovascular, inflammatory, and metabolic contexts due to their roles in vasodilation, fluid homeostasis, and tissue remodeling.