Nickel suppresses the PACAP-induced increase in guinea pig cardiac neuron excitability

• Published in: American Journal of Physiology: Cell Physiology 2015-06, Vol.308 (11), p.C857-C866
• Main Authors: Tompkins, John D, Merriam, Laura A, Girard, Beatrice M, May, Victor, Parsons, Rodney L
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels, R-Type - genetics; Calcium Channels, R-Type - metabolism; Calcium Channels, T-Type - genetics; Calcium Channels, T-Type - metabolism; Call for Papers; Cardiovascular system; Female; Gene Expression; Guinea Pigs; Male; Mibefradil - pharmacology; Microelectrodes; Myocardium - cytology; Myocardium - metabolism; Neurons; Neurons - cytology; Neurons - drug effects; Nickel; Nickel - pharmacology; Patch-Clamp Techniques; Pituitary Adenylate Cyclase-Activating Polypeptide - antagonists & inhibitors; Pituitary Adenylate Cyclase-Activating Polypeptide - pharmacology; Polymerase chain reaction; Polypeptides; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - genetics; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - metabolism; Rodents; Single-Cell Analysis
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00403.2014

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.