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J. Biol. Chem., Vol. 279, Issue 39, 40609-40621, September 24, 2004

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VPAC Receptor Modulation of Neuroexcitability in Intracardiac Neurons

DEPENDENCE ON INTRACELLULAR CALCIUM MOBILIZATION AND SYNERGISTIC ENHANCEMENT BY PAC₁ RECEPTOR ACTIVATION^*

Wayne I. DeHaven and Javier Cuevas

From the Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa, Florida 33612

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) have been found within mammalian intracardiac ganglia, but the cellular effects of these neuropeptides remain poorly understood. Fluorometric calcium imaging and whole cell patch clamp recordings were used to examine the effects of PACAP and VIP on [Ca²⁺]_i and neuroexcitability, respectively, in intracardiac neurons of neonatal rats. PACAP and VIP evoked rapid increases in [Ca²⁺]_i that exhibited both transient and sustained components. Pharmacological experiments using PAC₁ and VPAC receptor-selective antagonists demonstrated that the elevations in [Ca²⁺]_i result from the activation of VPAC receptors. The transient increases in [Ca²⁺]_i were shown to be the product of Ca²⁺ mobilization from caffeine/ryanodine-sensitive intracellular stores and were not due to inositol 1,4,5-trisphosphate-mediated calcium release. In contrast, the sustained [Ca²⁺]_i elevations were dependent on extracellular Ca²⁺ and were blocked by the transient receptor channel antagonist, 2-aminoethoxydiphenyl borate, which suggests that they are due to Ca²⁺ entry via store-operated channels. In addition to elevating [Ca²⁺]_i, both PACAP and VIP depolarized intracardiac neurons, and PACAP was further shown to augment action potential firing in these cells. Depolarization of intracardiac neurons by the neuropeptides was dependent on activation of VPAC receptors and the concomitant increases in [Ca²⁺]_i. Although activation of PAC₁ receptors alone had no direct effects on neuroexcitability, PAC₁ receptor stimulation potentiated the VPAC receptor-induced depolarizations. Furthermore, enhanced action potential firing was only observed upon concurrent stimulation of PAC₁ and VPAC receptors, which indicates that these receptors act synergistically to enhance neuroexcitability in intracardiac neurons.

Received for publication, April 28, 2004 , and in revised form, July 1, 2004.

^* This work was supported by National Institutes of Health Grant NIH RO1 HL63247 (to J. C.) and an American Heart Association Florida/Puerto Rico Affiliate predoctoral fellowship (to W. I. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC 9, Tampa, FL 33612-4799. Tel.: 813-974-4678; Fax: 813-974-2565; E-mail: jcuevas{at}hsc.usf.edu.

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