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J. Biol. Chem., Vol. 283, Issue 6, 3445-3453, February 8, 2008

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Homeostatic Regulation of Kv1.2 Potassium Channel Trafficking by Cyclic AMP^*

Emilee C. Connors, Bryan A. Ballif, and Anthony D. Morielli¹

From the Department of Pharmacology, College of Medicine, and the Department of Biology, University of Vermont, Burlington, Vermont 05405

The Shaker family potassium channel, Kv1.2, is a key determinant of membrane excitability in neurons and cardiovascular tissue. Kv1.2 is subject to multiple forms of regulation and therefore integrates cellular signals involved in the homeostasis of excitability. The cyclic AMP/protein kinase A (PKA) pathway enhances Kv1.2 ionic current; however, the mechanisms for this are not fully known. Here we show that cAMP maintains Kv1.2 homeostasis through opposing effects on channel trafficking. We found that Kv1.2 is regulated by two distinct cAMP pathways, one PKA-dependent and the other PKA-independent. PKA inhibitors elevate Kv1.2 surface levels, suggesting that basal levels of cAMP control steady-state turnover of the channel. Elevation of cAMP above basal levels also increases the amount of Kv1.2 at the cell surface. This effect is not blocked by PKA inhibitors, but is blocked by inhibition of Kv1.2 endocytosis. We conclude that Kv1.2 levels at the cell surface are kept in dynamic balance by opposing effects of cAMP.

Received for publication, October 29, 2007

^* This work was supported in part by National Institutes of Health Grant 5 P20 RR016435-07 from the Center of Biomedical Research Excellence Program of the National Center of Research Resources, by the Vermont Cancer Center of the Vermont Genetics Network through National Institutes of Health Grant P20 RR16462 from the Institutional Development Award Networks of Biomedical Research Excellence Program of the National Center for Research Resources (to B. A. B.), and by National Institutes of Health Grant R0NS050623 (to A. D. M.). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, College of Medicine, University of Vermont, Given Bldg., Rm. E-317, 89 Beaumont Ave., Burlington, VT 05405. Tel.: 802-656-4500; Fax: 802-656-4523; E-mail: anthony.morielli{at}uvm.edu.

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