title: Nickel suppresses the PACAP-induced increase in guinea pig cardiac neuron excitability.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent intercellular signaling molecule involved in multiple homeostatic functions. PACAP/PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, making them a unique system to establish mechanisms underlying PACAP modulation of neuronal function. Calcium influx is required for the PACAP-increased cardiac neuron excitability, although the pathway is unknown. This study tested whether PACAP enhancement of calcium influx through either T-type or R-type channels contributed to the modulation of excitability. Real-time quantitative polymerase chain reaction analyses indicated transcripts for Cav3.1, Cav3.2, and Cav3.3 T-type isoforms and R-type Cav2.3 in cardiac neurons. These neurons often exhibit a hyperpolarization-induced rebound depolarization that remains when cesium is present to block hyperpolarization-activated nonselective cationic currents (Ih). The T-type calcium channel inhibitors, nickel (Ni(2+)) or mibefradil, suppressed the rebound depolarization, and treatment with both drugs hyperpolarized cardiac neurons by 2-4 mV. Together, these results are consistent with the presence of functional T-type channels, potentially along with R-type channels, in these cardiac neurons. Fifty micromolar Ni(2+), a concentration that suppresses currents in both T-type and R-type channels, blunted the PACAP-initiated increase in excitability. Ni(2+) also blunted PACAP enhancement of the hyperpolarization-induced rebound depolarization and reversed the PACAP-mediated increase in excitability, after being initiated, in a subset of cells. Lastly, low voltage-activated currents, measured under perforated patch whole cell recording conditions and potentially flowing through T-type or R-type channels, were enhanced by PACAP. Together, our results suggest that a PACAP-enhanced, Ni(2+)-sensitive current contributes to PACAP-induced modulation of neuronal excitability.
authors: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont.
authors: John D
authors: JD
authors: Tompkins
authors: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont.
authors: Laura A
authors: LA
authors: Merriam
authors: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont.
authors: Beatrice M
authors: BM
authors: Girard
authors: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont.
authors: Victor
authors: V
authors: May
authors: Department of Neurological Sciences, College of Medicine, University of Vermont, Burlington, Vermont rodney.parsons@uvm.edu.
authors: Rodney L
authors: RL
authors: Parsons
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020908:Calcium Channels, R-Type / Q000235:genetics / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006168:Guinea Pigs; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D008839:Microelectrodes; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009532:Nickel / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics / Q000378:metabolism; D059010:Single-Cell Analysis
chemical_list: D002121:Calcium Channel Blockers; D020908:Calcium Channels, R-Type; D020747:Calcium Channels, T-Type; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020033:Protein Isoforms; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D020748:Mibefradil; D009532:Nickel; D002118:Calcium
keywords: PACAP; autonomic neuron; low voltage-activated calcium currents; neuronal excitability