title: Activation of MEK/ERK signaling contributes to the PACAP-induced increase in guinea pig cardiac neuron excitability.
abstract: Pituitary adenylate cyclase (PAC)-activating polypeptide (PACAP) peptides (Adcyap1) signaling at the selective PAC1 receptor (Adcyap1r1) participate in multiple homeostatic and stress-related responses, yet the cellular mechanisms underlying PACAP actions remain to be completely elucidated. PACAP/PAC1receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, and as these neurons are readily accessible, this neuronal system is particularly amenable to study of PACAP modulation of ionic conductances. The present study investigated how PACAP activation of MEK/ERK signaling contributed to the peptide-induced increase in cardiac neuron excitability. Treatment with the MEK inhibitor PD 98059 blocked PACAP-stimulated phosphorylated ERK and, in parallel, suppressed the increase in cardiac neuron excitability. However, PD 98059 did not blunt the ability of PACAP to enhance two inward ionic currents, one flowing through hyperpolarization-activated nonselective cationic channels (Ih) and another flowing through low-voltage-activated calcium channels (IT), which support the peptide-induced increase in excitability. Thus a PACAP- and MEK/ERK-sensitive, voltage-dependent conductance(s), in addition to Ihand IT, modulates neuronal excitability. Despite prior work implicating PACAP downregulation of the KV4.2 potassium channel in modulation of excitability in other cells, treatment with the KV4.2 current blocker 4-aminopyridine did not replicate the PACAP-induced increase in excitability in cardiac neurons. However, cardiac neurons express the ERK target, the NaV1.7 sodium channel, and treatment with the selective NaV1.7 channel inhibitor PF-04856264 decreased the PACAP modulation of excitability. From these results, PACAP/PAC1 activation of MEK/ERK signaling may phosphorylate the NaV1.7 channel, enhancing sodium currents near the threshold, an action contributing to repetitive firing of the cardiac neurons exposed to PACAP.
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: John D
authors.initials: JD
authors.lastname: Tompkins
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Clason
authors.affiliation: Biology Department, Ithaca College, Ithaca, New York.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Hardwick
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Girard
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Merriam
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Victor
authors.initials: V
authors.lastname: May
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and Rodney.Parsons@med.uvm.edu.
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Parsons
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000378:metabolism; D051672:Shal Potassium Channels / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D062556:NAV1.7 Voltage-Gated Sodium Channel; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051672:Shal Potassium Channels
keywords: MAPK signaling; PKA; autonomic neuron; neuronal excitability; pituitary adenylate cyclase-activating polypeptide