Multiple Mechanisms Contribute to the PAC1 Modulation of Parasympathetic Cardiac Neuron Excitability

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent intercellular signaling molecule that regulates a variety of central and peripheral neuronal circuits important for behavior and physiological homeostasis. Although central neurons are not readily accessible for mechanistic studies, the ability for PACAP/PAC1 receptor signaling to increase neuronal excitability in guinea pig parasympathetic cardiac ganglia provides a unique means to establish intracellular PACAP mechanisms in neuronal function. The guinea pig cardiac neurons predominantly express a very short null PAC1 receptor isoform which is coupled to the adenylyl cyclase and MEK/ERK signaling cascades. PACAP/PAC1 receptor activation of adenylyl cyclase and the resulting rise in intracellular cAMP enhances the nonselective cationic current Ih; treatment with Ih inhibitors diminishes the PACAP-induced increase in excitability. Thus, a shift in the voltage-dependence of Ih activation is one ionic mechanism contributing to the PACAP-induced increase in cardiac neuron excitability. Low concentrations of nickel also blunt the peptide-induced increase in excitability, suggesting that a PACAP enhanced calcium influx through T-type voltage-dependent calcium channels contributes to the modulation of excitability. Reducing ambient temperature and treatments with endocytosis inhibitors Pitstop2 or dynasore efficaciously block PACAP modulation of excitability suggesting PACAP/PAC1 receptor internalization for endosomal MEK/ERK activation is requisite for the PACAP responses. In sum, the results presented in this review demonstrate that the PACAP/PAC1 receptor interactions can activate multiple intracellular signaling cascades to selectively modulate ionic conductances that gate neuronal excitability.