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J. Biol. Chem., Vol. 279, Issue 44, 45455-45461, October 29, 2004

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Ca²+-induced Ca²+ Release via Inositol 1,4,5-trisphosphate Receptors Is Amplified by Protein Kinase A and Triggers Exocytosis in Pancreatic -Cells^*

Oleg Dyachok and Erik Gylfe¶

From the Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden and the Department of Biophysics, National T. Shevchenko University of Kiev, Kiev, Ukraine

Hormones, such as glucagon and glucagon-like peptide-1, potently amplify nutrient stimulated insulin secretion by raising cAMP. We have studied how cAMP affects Ca²⁺-induced Ca²⁺ release (CICR) in pancreatic -cells from mice and rats and the role of CICR in secretion. CICR was observed as pronounced Ca²⁺ spikes on top of glucose- or depolarization-dependent rise of the cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i). cAMP-elevating agents strongly promoted CICR. This effect involved sensitization of the receptors underlying CICR, because many cells exhibited the characteristic Ca²⁺ spiking at low or even in the absence of depolarization-dependent elevation of [Ca²⁺]_i. The cAMP effect was mimicked by a specific activator of protein kinase A in cells unresponsive to activators of cAMP-regulated guanine nucleotide exchange factor. Ryanodine pretreatment, which abolishes CICR mediated by ryanodine receptors, did not prevent CICR. Moreover, a high concentration of caffeine, known to activate ryanodine receptors independently of Ca²⁺, failed to mobilize intracellular Ca²⁺. On the contrary, a high caffeine concentration abolished CICR by interfering with inositol 1,4,5-trisphosphate receptors (IP₃Rs). Therefore, the cell-permeable IP₃R antagonist 2-aminoethoxydiphenyl borate blocked the cAMP-promoted CICR. Individual CICR events in pancreatic -cells were followed by [Ca²⁺]_i spikes in neighboring human erythroleukemia cells, used to report secretory events in the -cells. The results indicate that protein kinase A-mediated promotion of CICR via IP₃Rs is part of the mechanism by which cAMP amplifies insulin release.

Received for publication, July 8, 2004 , and in revised form, August 11, 2004.

^* This work was supported by Grant 06240 from the Swedish Research Council, and grants from the Swedish Diabetes Association, the Scandinavian Physiological Society, the Family Ernfors foundation and the Knut and Alice Wallenberg Foundation. 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. Tel.: 46-18-4714428; Fax: 46-18-4714059; E-mail: erik.gylfe{at}medcellbiol.uu.se.

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