Parallel signaling pathways of pituitary adenylate cyclase activating polypeptide (PACAP) regulate several intrinsic ion channels

Abstract

Pituitary adenylate cyclase activating polypeptide acting through its cognate receptors, PAC1, VPAC1, and VPAC2, is a pleiotropic signaling neuropeptide of the vasoactive intestinal peptide/secretin/glucagon family. PACAP has known functions in neuronal growth, development, repair, and central PACAP signaling has acute behavioral consequences. One of the ways in which PACAP may affect neuronal function is through the modulation of intrinsic membrane currents to control neuronal excitability. Here we review evidence of PACAP-dependent modulation of voltage-gated potassium currents, hyperpolarization activated cation currents, calcium currents, and voltage-gated sodium currents. Interestingly, PACAP signaling pathways diverge into parallel pathways to target different ionic currents for modulation, though single pathways are not limited to modulating just one target ionic current. Despite the various targets of modulation, the weight of the evidence suggests that PACAP signaling most commonly leads to a net-increase in neuronal excitability. We discuss possible mechanisms by which PACAP signaling leads to the modulation of intrinsic membrane currents to change behavior.

Behavioral role of PACAP signaling reflects its selective distribution in glutamatergic and GABAergic neuronal subpopulations

“…Activity-dependent regulation of both glutamate and GABA vesicular transporter synthesis and membrane insertion has been reported (De Gois, Schafer et al 2005, Erickson, De Gois et al 2006, Doyle, Pyndiah et al 2010. PACAP signaling most commonly leads to a net increase in neuronal excitability through modulation of intrinsic membrane currents and transiently increasing intracellular calcium concentration (Johnson, May et al 2019). Decreased vesicular transporter mRNA expression would be expected at the cellular level to decrease transmitter quantal size, thus decreasing excitatory/inhibitory postsynaptic currents (EPSCs and IPSCs respectively) (Billups 2005), and is consistent with our behavior data.…”

“…PACAP binding to PAC1 receptors initiates signaling through multiple intracellular pathways. PACAP/PAC1 signaling is generally considered to engage Gαs, activating adenylate cyclase, and Gαq, activating phospholipase C, and leads to multiple cellular responses including increased neuronal excitability (Kawasaki, Springett et al 1998, Emery, Eiden et al 2013, Jiang, Xu et al 2017, Johnson, May et al 2019. The PACAP/PAC1 signaling pathway has consistently been related to psychogenic stress responding, and potentiation of this pathway has been linked to psychopathologies including anxiety and PTSD in human (Ressler, Mercer et al 2011, Wang, Cao et al 2013, Mustafa, Jiang et al 2015.…”

Progress in regulatory peptide research

“…PACAP is an important neurotransmitter peripherally, in both the sympathetic and parasympathetic branches of the autonomic nervous system, and in the brain mediates hedonic tone, anxiety, and sociability as a function of stress. Hammack and colleagues summarize the cellular actions of PACAP in cholinergic preganglionic neurons, and elsewhere, at the level of intrinsic ion channel regulation. Their pithy summary of these effects is noteworthy, as these may be paradigmatic for the actions of other peptides at the cellular level.…”

“…Although most peptides are notable as hormone and transmitter secretagogues, they mediate secretion and other cellular actions, including gene regulation, via mechanisms quite distinct from ionotropic receptors. Rather than directly regulating the open and closed states of ion channels in excitable cells, PACAP, like many other peptide GPCRs, affects ion channel function metabotropically, that is, via intracellular mechanisms rather than direct “gating” of the channels themselves . This provides a completely different time scale to peptide effects on excitability, and one that must be considered in the context of the “primary” regulators of excitability, such as acetylcholine in the mammalian peripheral nervous system, and acetylcholine and glutamate in the mammalian central nervous system.…”

Behavioral role of PACAP signaling reflects its selective distribution in glutamatergic and GABAergic neuronal subpopulations

“…PACAP binding to its receptors Vipr1, Vipr2 and, predominantly, PAC1 initiates cell signaling through multiple intracellular pathways ( Harmar, 2001 ). PACAP acting at PAC1 is generally considered to engage Gαs, activating adenylate cyclase, with some isoforms also activating phospholipase C via Gαq, leading to multiple cellular responses including increased neuronal excitability ( Pisegna and Wank, 1993 ; Spengler et al, 1993 ; Kawasaki et al, 1998 ; Emery et al, 2013 ; Jiang et al, 2017 ; Johnson et al, 2019 ). The PACAP/PAC1 signaling pathway has consistently been related to psychogenic stress responding, and potentiation of this pathway has been linked to psychopathologies including anxiety and PTSD in human ( Ressler et al, 2011 ; Wang et al, 2013a ; Mustafa et al, 2015 ).…”