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J. Biol. Chem., Vol. 280, Issue 31, 28692-28700, August 5, 2005

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A Novel Mechanism for the Suppression of a Voltage-gated Potassium Channel by Glucose-dependent Insulinotropic Polypeptide

PROTEIN KINASE A-DEPENDENT ENDOCYTOSIS^*

Su-Jin Kim, Woo Sung Choi, John Song Mou Han, Garth Warnock¶, David Fedida, and Christopher H. S. McIntosh||

From the Departments of Cellular & Physiological Sciences and ^¶Surgery, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

The mechanisms involved in glucose regulation of insulin secretion by ATP-sensitive (K_ATP) and calcium-activated (K_CA) potassium channels have been extensively studied, but less is known about the role of voltage-gated (K_V) potassium channels in pancreatic -cells. The incretin hormone, glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion by potentiating events underlying membrane depolarization and exerting direct effects on exocytosis. In the present study, we identified a novel role for GIP in regulating K_V1.4 channel endocytosis. In GIP receptor-expressing HEK293 cells, GIP reduced A-type peak ionic current amplitude of K_V1.4 via activation of protein kinase A (PKA). Using mutant forms of K_V1.4 with Ala-Ser/Thr substitutions in a potential PKA phosphorylation site, C-terminal phosphorylation was shown to be linked to GIP-mediated current amplitude decreases. Proteinase K digestion and immunocytochemical studies on mutant K_V1.4 localization following GIP stimulation demonstrated phosphorylation-dependent rapid endocytosis of K_V1.4. Expression of K_V1.4 protein was also demonstrated in human -cells; GIP treatment resulting in similar decreases in A-type potassium current peak amplitude to those in HEK293 cells. Transient overexpression in INS-1 -cells (clone 832/13) of wild-type (WT) K_V1.4, or a T601A mutant form resistant to PKA phosphorylation, resulted in reduced glucose-stimulated insulin secretion; WT K_V1.4 overexpression potentiated GIP-induced insulin secretion, whereas this response was absent in T601A cells. These results strongly support an important novel role for GIP in regulating K_V1.4 cell surface expression and modulation of A-type potassium currents, which is likely to be critically important for its insulinotropic action.

Received for publication, May 4, 2005 , and in revised form, June 8, 2005.

^* This work was supported by the Canadian Institutes of Health Research (CIHR) (Grant 590007), the Canadian Diabetes Association, and the Canadian Foundation for Innovation (CFI) (to C. H. S. M.); by the CIHR and the Michael Smith Foundation (to D. F.); by the CFI P. A. Woodward Foundation and the Ike Barber Diabetes Research Endowment (to G. W.); and by a University Graduate Fellowship (to W. S. C.). 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.

Both authors equally contributed to this work.

^|| To whom correspondence should be addressed: Dept. of Cellular & Physiological Sciences, Faculty of Medicine, University of British Columbia, 2146 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Tel.: 604-822-3088; Fax: 604-822-6048; E-mail: mcintoch{at}interchange.ubc.ca.

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