Fig. 6.

Schematic of intracellular signaling cascades and ionic conductances potentially contributing to the PACAP-induced increase in cardiac neuron excitability. Interaction of PACAP with the PAC₁ receptor (1) leads to activation of adenylyl cyclase (AC) and generation of cAMP (2). The rise of cAMP and interaction with hyperpolarization-activated cyclic nucleotide-gated channels enhance hyperpolarization-activated nonselective cationic current (I_h) (3), and a rise in cAMP also activates PKA (4), enhancing T-type channel currents through protein phosphorylation (5) and possibly contributes to activation of MEK/ERK signaling (6). Internalization of the PACAP/PAC₁ receptor complex and formation of a signaling endosome (7) provides a scaffold for recruitment of the MEK/ERK signaling cascade (8), and activation of MEK/ERK kinase signaling potentially alters the voltage-dependent Na⁺ channel Na_V1.7 through protein phosphorylation (9). For other cell types, a PACAP-induced decrease in surface expression of K_V4.2 (dashed line 9) could also contribute to the increased excitability. Gαs, G protein α-subunit.