Fig. 3

Schematic of CGRP and PACAP signaling pathways. CGRP and PACAP can act via multiple receptors, as indicated. For simplicity, signaling pathways from generic receptors in a generic cell type are illustrated. In general, activation of both CGRP and PACAP receptors increase cAMP levels, which leads to protein kinase A (PKA) activation and EPAC1/2 activation. EPAC1/2 activation by PACAP is well-established, although activation by CGRP is less clear (dotted line). Canonical CGRP receptor, but not AMY₁ CGRP receptor, and the PACAP receptor PAC₁ can generate endosomal signals following β-arrestin-mediated receptor internalization. Activation of additional G protein pathways that elevate IP₃ and calcium have been reported for PACAP and to a lesser extent CGRP (dotted lines). These pathways activate multiple downstream targets, including MAP kinases (MAPKs), ion channels, and genes, depending on the cell type. Created with BioRender.com