Journal of Biological Chemistry
Volume 277, Issue 2, 11 January 2002, Pages 1340-1348
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MECHANISMS OF SIGNAL TRANSDUCTION
Phosphorylation of Inositol 1,4,5-Trisphosphate Receptors in Parotid Acinar Cells: A MECHANISM FOR THE SYNERGISTIC EFFECTS OF cAMP ON Ca2+ SIGNALING*

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Acetylcholine-evoked secretion from the parotid gland is substantially potentiated by cAMP-raising agonists. A potential locus for the action of cAMP is the intracellular signaling pathway resulting in elevated cytosolic calcium levels ([Ca2+]i). This hypothesis was tested in mouse parotid acinar cells. Forskolin dramatically potentiated the carbachol-evoked increase in [Ca2+]i, converted oscillatory [Ca2+]i changes into a sustained [Ca2+]i increase, and caused subthreshold concentrations of carbachol to increase [Ca2+]i measurably. This potentiation was found to be independent of Ca2+ entry and inositol 1,4,5-trisphosphate (InsP3) production, suggesting that cAMP-mediated effects on Ca2+ release was the major underlying mechanism. Consistent with this hypothesis, dibutyryl cAMP dramatically potentiated InsP3-evoked Ca2+release from streptolysin-O-permeabilized cells. Furthermore, type II InsP3 receptors (InsP3R) were shown to be directly phosphorylated by a protein kinase A (PKA)-mediated mechanism after treatment with forskolin. In contrast, no evidence was obtained to support direct PKA-mediated activation of ryanodine receptors (RyRs). However, inhibition of RyRs in intact cells, demonstrated a role for RyRs in propagating Ca2+ oscillations and amplifying potentiated Ca2+ release from InsP3Rs. These data indicate that potentiation of Ca2+ release is primarily the result of PKA-mediated phosphorylation of InsP3Rs, and may largely explain the synergistic relationship between cAMP-raising agonists and acetylcholine-evoked secretion in the parotid. In addition, this report supports the emerging consensus that phosphorylation at the level of the Ca2+ release machinery is a broadly important mechanism by which cells can regulate Ca2+-mediated processes.

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Published, JBC Papers in Press, November 1, 2001, DOI 10.1074/jbc.M106609200

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This work was supported by National Institutes of Health Grants DEO 13539 (to T. J. S. and D. I. Y.), GM 40457 (to T. J. S.), and DK54568 (to D. I. Y.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.