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J. Biol. Chem., Vol. 279, Issue 36, 37291-37297, September 3, 2004

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Modulation of L-type Calcium Channels in Drosophila via a Pituitary Adenylyl Cyclase-activating Polypeptide (PACAP)-mediated Pathway^*

Anindya Bhattacharya, Sukhwinder S. Lakhman, and Satpal Singh¶

From the Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York 14214-3000

Modulation of calcium channels plays an important role in many cellular processes. Previous studies have shown that the L-type Ca²⁺ channels in Drosophila larval muscles are modulated via a cAMP-protein kinase A (PKA)-mediated pathway. This raises questions on the identity of the steps prior to cAMP, particularly the endogenous signal that may initiate this modulatory cascade. We now present data suggesting the possible role of a neuropeptide, pituitary adenylyl cyclase-activating polypeptide (PACAP), in this modulation. Mutations in the amnesiac (amn) gene, which encodes a polypeptide homologous to human PACAP-38, reduced the L-type current in larval muscles. Conditional expression of a wild-type copy of the amn gene rescued the current from this reduction. Bath application of human PACAP-38 also rescued the current. PACAP-38 did not rescue the mutant current in the presence of PACAP-6–38, an antagonist at type-I PACAP receptor. 2',5'-dideoxyadenosine, an inhibitor of adenylyl cyclase, prevented PACAP-38 from rescuing the amn current. In addition, 2',5'-dideoxyadenosine reduced the wild-type current to the level seen in amn, whereas it failed to further reduce the current observed in amn muscles. H-89, an inhibitor of PKA, suppressed the effect of PACAP-38 on the current. The above data suggest that PACAP, the type-I PACAP receptors, and adenylyl cyclase play a role in the modulation of L-type Ca²⁺ channels via cAMP-PKA pathway. The data also provide support for functional homology between human PACAP-38 and the amn gene product in Drosophila.

Received for publication, April 6, 2004 , and in revised form, June 15, 2004.

^* This work was supported by National Institutes of Health Grant GM-50779 and National Science Foundation Grant MCB-0094477. 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.

Present address: Roche Pharmaceuticals, 3431 Hillview Ave., R2-101, Palo Alto, CA 94304.

Present address: Dept. of Pharmaceutical Sciences, 527 Cooke Hall, State University of New York at Buffalo, NY 14260-1200.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, 102 Farber Hall, State University of New York at Buffalo, Buffalo, NY 14214-3000. Tel.: 716-829-2453; Fax: 716-829-2801; E-mail: singhs{at}buffalo.edu.

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