What makes a CGRP2 receptor?

Heterogeneity in the receptors for the neuropeptide calcitonin gene-related peptide (CGRP) has been apparent for nearly 20 years. This is most clearly manifested in the observation of CGRP(8-37)-sensitive and -insensitive populations of CGRP-activated receptors. The pA(2) values for CGRP(8-37) in excess of 7 are widely considered to be the result of antagonism of CGRP(1) receptors, whereas those below 7 are believed to be the consequence of antagonism of a second population of receptors, namely CGRP(2) receptors. However, a multitude of pA(2) values exist for CGRP(8-37), spanning several log units, and as such no obvious clusters of values are apparent. Understanding the molecular nature of the receptors that underlie this phenomenon is likely to aid the development of selective pharmacological tools to progress our understanding of the physiology of CGRP and related peptides. Because there is active development of CGRP agonists and antagonists as therapeutics, such information would also further this pursuit. The CGRP(1) receptor is pharmacologically and molecularly well defined as a heterodimer of the calcitonin receptor-like receptor (CL) and receptor activity modifying protein (RAMP) 1. The CL/RAMP1 complex is highly sensitive to CGRP(8-37). Conversely, the constituents of the CGRP(2) receptor have not been identified. In fact, there is little evidence for a distinct molecular entity that represents the CGRP(2) receptor. Recent pharmacological characterization of receptors related to CGRP(1) has revealed that some of these receptors may explain CGRP(2) receptor pharmacology. Specifically, AMY(1(a)) (calcitonin receptor/RAMP1) and AM(2) (CL/RAMP3) receptors can be activated by CGRP but are relatively insensitive to CGRP(8-37). This, along with other supporting data, suggests that the 'CGRP(2) receptor' that has been extensively reported in the literature may, in fact, be an amalgamation of contributions from a variety of CGRP-activated receptors. The use of appropriate combinations of agonists and antagonists, along with receptor expression studies, could allow such receptors to be separated.