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Enhancement of I_h, but not inhibition of I_M, is a key mechanism underlying the PACAP-induced increase in excitability of guinea pig intrinsic cardiac neurons

Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, Burlington, Vermont

Submitted 21 January 2009 ; accepted in final form 23 April 2009

Pituitary adenylate cyclase-activating polypeptide (PACAP) increases excitability of guinea pig cardiac neurons, an effect mediated by PACAP-selective PAC₁ receptors. In dissociated guinea pig cardiac neurons, PACAP causes a positive shift of the voltage dependence of activation of the hyperpolarization-activated nonselective cation current (I_h). This observation suggested that an enhancement of I_h contributed to the increase in excitability in neurons within whole-mount cardiac ganglia preparations. To evaluate the role of I_h in the PACAP-induced increase in excitability, we compared the increase in action potentials generated by 10 nM PACAP in control neurons and in neurons treated with ZD7288 (10 or 100 µM) or CsCl (2 or 2.5 mM), drugs known to inhibit I_h. In control cells exposed to PACAP, 1-s depolarizing current pulses elicited multiple action potential firing in 79% of the neurons. In ZD7288- or CsCl-containing solutions, the 10 nM PACAP-induced increase in excitability was markedly suppressed, with 7% and 21% of the neurons generating multiple action potentials, respectively. Prior results indicated that PACAP initiates depolarization by activating an inward current, which is separate from its enhancement of I_h. Here, we show that a PACAP-induced depolarization was comparable in control neurons and neurons bathed in a CsCl-containing solution, an observation indicating that CsCl did not interfere with activation of the PAC₁ receptor by PACAP. Additional experiments indicated that pretreatment with the putative M current (I_M) inhibitor 1 mM BaCl₂, but not 10 µM XE991, initiated multiple firing in a majority of neurons, with resting potentials maintained at approximately –60 mV. Furthermore, in Ba²⁺-treated cells, 10 nM PACAP increased the number of action potentials generated. Our results indicate that PACAP enhancement of I_h, rather than inhibition of I_M and other 1 mM Ba²⁺-sensitive K⁺ currents, is a key ionic mechanism contributing to the peptide-induced increase in excitability for neurons within whole-mount cardiac ganglia preparations.

hyperpolarization-activated nonselective cation current; neuronal excitability; neuropeptide; parasympathetic neurons