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J. Biol. Chem., Vol. 279, Issue 38, 39485-39494, September 17, 2004

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cAMP Potentiates ATP-evoked Calcium Signaling in Human Parotid Acinar Cells^*

David A. Brown, Jason I. E. Bruce, Stephen V. Straub, and David I. Yule

From the Department of Pharmacology & Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York 14642

In salivary acinar cells, intracellular calcium ([Ca²⁺]_i) signaling plays an important role in eliciting fluid secretion through the activation of Ca²⁺-activated ionic conductances. Ca²⁺ and cAMP have synergistic effects on fluid secretion such that peak secretion is elicited following activation of both parasympathetic and sympathetic pathways. We have recently demonstrated that cAMP exerts effects on Ca²⁺ release, through protein kinase A (PKA)-mediated phosphorylation of inositol 1,4,5-trisphosphate receptors (InsP₃R) in mouse parotid acinar cells. To extend these findings, in the present study cross-talk between Ca²⁺ signaling and cAMP pathways in human parotid acinar cells was investigated. In human parotid acinar cells, carbachol stimulation evoked increases in the [Ca²⁺]_i and the initial peak amplitude was enhanced following PKA activation, consistent with reports from mouse parotid. Stimulation with ATP also evoked an increase in [Ca²⁺]_i. The ATP-evoked Ca²⁺ elevation was largely dependent on extracellular Ca²⁺, suggesting the involvement of the P2X family of purinergic receptors. Pharmacological elevation of cAMP resulted in a 5-fold increase in the peak [Ca²⁺]_i change evoked by ATP stimulation. This enhanced [Ca²⁺]_i increase was not dependent on intracellular release from InsP₃R or ryanodine receptors, suggesting a direct effect on P2XR. Reverse transcription-polymerase chain reaction and Western blot analysis confirmed the presence of P2X₄R and P2X₇R mRNA and protein in human parotid acinar cells. ATP-activated cation currents were studied using whole cell patch clamp techniques in HEK-293 cells, a null background for P2XR. Raising cAMP resulted in a 4.5-fold enhancement of ATP-activated current in HEK-293 cells transfected with P2X₄R DNA but had no effects on currents in cells expressing P2X₇R. These data indicate that in human parotid acinar cells, in addition to modulation of Ca²⁺ release, Ca²⁺ influx through P2X₄R may constitute a further locus for the synergistic effects of Ca²⁺ and PKA activation.

Received for publication, June 3, 2004

^* This work was supported in part by Grants R01-DK-54568, R01-DE14756, and PO1-DE13539 from the National Institutes of Health (to D. I. Y.). 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.

Supported by NIDCR, National Institutes of Health Training Grant T32-DE-07202.

To whom correspondence should be addressed: Dept. of Pharmacology & Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Ave., Rochester NY 14642. Tel.: 585-275-6128; Fax: 585-273-2652; E-mail: David_Yule{at}urmc.rochester.edu.

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