Reply to comment on: A second trigeminal CGRP receptor: function and expression of the AMY1 receptor.

In their comment, Haanes et al., suggest that CGRP could act through two distinct receptors in human coronary arteries; namely the CGRP receptor (CLR/RAMP1) and the AMY1 receptor (CTR/RAMP1). 1 Although there are other possible explanations, the presence of multiple CGRP receptor subtypes could explain their elegant data. In light of the active clinical development of blocking antibodies and small molecules against either CGRP or CLR/RAMP1, this interesting proposition warrants further investigation. Although Haanes et al., are correct that IUPHAR does not officially recognize a single molecular entity named as the “CGRP2 receptor,” the numerous pharmacological activities of CGRP and its receptor heterogeneity are well documented in IUPHAR publications, following-on from initial observations by Remi Quirion, Ian Marshall, David Poyner, Patrick Sexton, and coworkers. The first amylin receptor studies following the discovery of RAMPs showed that aCGRP and amylin could equivalently displace I-amylin from the AMY1 receptor (CTR/RAMP1). It was subsequently noted that the ‘CGRP2’ subtype was likely the AMY1 receptor with possible contributions also by the AMY3 (CTR/RAMP3) and AM2 (CLR/RAMP3) receptors, depending on species. 6