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J. Biol. Chem., Vol. 278, Issue 52, 52446-52453, December 26, 2003

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Antagonism of Rat -Cell Voltage-dependent K⁺ Currents by Exendin 4 Requires Dual Activation of the cAMP/Protein Kinase A and Phosphatidylinositol 3-Kinase Signaling Pathways^*

Patrick E. MacDonald, Xiaolin Wang¶, Fuzhen Xia||, Wasim El-kholy**, Elisha D. Targonsky, Robert G. Tsushima||, and Michael B. Wheeler, CIHR Investigator.||

From the Departments of Physiology and ^||Medicine, University of Toronto, Toronto, Ontario M1H 1E6, Canada

Antagonism of voltage-dependent K⁺ (Kv) currents in pancreatic -cells may contribute to the ability of glucagon-like peptide-1 (GLP-1) to stimulate insulin secretion. The mechanism and signaling pathway regulating these currents in rat -cells were investigated using the GLP-1 receptor agonist exendin 4. Inhibition of Kv currents resulted from a 20-mV leftward shift in the voltage dependence of steady-state inactivation. Blocking cAMP or protein kinase A (PKA) signaling (Rp-cAMP and H-89, respectively) prevented the inhibition of currents by exendin 4. However, direct activation of this pathway alone by intracellular dialysis of cAMP or the PKA catalytic subunit (cPKA) could not inhibit currents, implicating a role for alternative signaling pathways. A number of phosphorylation sites associated with phosphatidylinositol 3 (PI3)-kinase activation were up-regulated in GLP-1-treated MIN6 insulinoma cells, and the PI3 kinase inhibitor wortmannin could prevent antagonism of -cell currents by exendin 4. Antagonists of Src family kinases (PP1) and the epidermal growth factor (EGF) receptor (AG1478) also prevented current inhibition by exendin 4, demonstrating a role for Src kinase-mediated trans-activation of the EGF tyrosine kinase receptor. Accordingly, the EGF receptor agonist betacellulin could replicate the effects of exendin 4 in the presence of elevated intracellular cAMP. Downstream, the PKC pseudosubstrate inhibitor could prevent current inhibition by exendin 4. Therefore, antagonism of -cell Kv currents by GLP-1 receptor activation requires both cAMP/PKA and PI3 kinase/PKC signaling via trans-activation of the EGF receptor. This represents a novel dual pathway for the control of Kv currents by G protein-coupled receptors.

Received for publication, July 15, 2003 , and in revised form, October 3, 2003.

^* This work was supported in part by research grants from the Canadian Institutes of Health Research (CIHR; MOP-49521) and the Canadian Diabetes Association (to M. B. W.). 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.

CIHR Fellow. Present address: Dept. of Molecular and Cellular Physiology, Lund University, Lund 22184, Sweden.

^¶ Supported by a CIHR New Emerging Team Grant in Diabetes Complications.

^** Supported by a Novo Nordisk Studentship from the Banting and Best Diabetes Centre.

To whom correspondence should be addressed: Dept. of Physiology, University of Toronto, 1 Kings College Circle, Rm. 3352, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-6737; Fax: 416-978-4940; E-mail: michael.wheeler{at}utoronto.ca.

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