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J. Biol. Chem., Vol. 282, Issue 40, 29612-29620, October 5, 2007

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Rab-GTPase-dependent Endocytic Recycling of KV1.5 in Atrial Myocytes^*

From the Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109

The number of ion channels expressed on the cell surface shapes the complex electrical response of excitable cells. Maintaining a balance between anterograde and retrograde trafficking of channel proteins is vital in regulating steady-state cell surface expression. Kv1.5 is an important voltage-gated K⁺ channel in the cardiovascular system underlying the ultra-rapid rectifying potassium current (Ik_ur), a major repolarizing current in atrial myocytes, and regulating the resting membrane potential and excitability of smooth muscle cells. Defects in the expression of Kv1.5 are associated with pathological states such as chronic atrial fibrillation and hypoxic pulmonary hypertension. There is, thus, substantial interest in understanding the mechanisms regulating cell surface channel levels. Here, we investigated the internalization and recycling of Kv1.5 in the HL-1 immortalized mouse atrial myocytes. Kinetic studies indicate that Kv1.5 is rapidly internalized to a perinuclear region where it co-localizes with the early endosomal marker, EEA1. Importantly, we identified that a population of Kv1.5, originating on the cell surface, internalized and recycled back to the plasma membrane. Notably, Kv1.5 recycling processes are driven by specific Rab-dependent endosomal compartments. Thus, co-expression of GDP-locked Rab4S22N and Rab11S25N dominant-negative mutants decreased the steady-state Kv1.5 surface levels, whereas GTPase-deficient Rab4Q67L and Rab11Q70L mutants increased steady-state Kv1.5 surface levels. These data reveal an unexpected dynamic trafficking of Kv1.5 at the myocyte plasma membrane and demonstrate a role for recycling in the maintenance of steady-state ion channel surface levels.

Received for publication, May 29, 2007 , and in revised form, July 31, 2007.

^* This research was supported by National Institutes of Health Grant HL0270973 (to J. R. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, 1301 MSRBIII, 1150 West Medical Center Dr., Ann Arbor, MI 48109-5632. Tel.: 734-615-9026; Fax: 734-763-4450; E-mail: martensj{at}umich.edu.

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