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First published on November 28, 2007; DOI: 10.1124/mol.107.042093

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Received for publication September 26, 2007.
Revised November 20, 2007.
Accepted for publication November 27, 2007.

Caveolin Regulates Kv1.5 Trafficking to Cholesterol-Rich Membrane Microdomains

Dyke P McEwen 1, Qiuju Li 1, Sajida Jackson 1, Paul M Jenkins 1, Jeffrey R Martens 1*

1 University of Michigan

* Address correspondence to: E-mail: martensj{at}umich.edu

Abstract

The targeting of ion channels to cholesterol-rich membrane microdomains has emerged as a novel mechanism of ion channel localization. Previously, we reported that Kv1.5, a prominent cardiovascular K+ channel {alpha}-subunit, localizes to caveolar microdomains. However, the mechanisms regulating Kv1.5 targeting and the functional significance of this localization are largely unknown. In this study, we demonstrate a role for caveolin in the trafficking of Kv1.5 to lipid raft microdomains where cholesterol modulates channel function. In cells lacking endogenous caveolin-1 or caveolin-3, the association of Kv1.5 with low-density, detergent-resistant membrane fractions requires co-expression with exogenous caveolin, which can form channel-caveolin complexes. Caveolin is not required for cell surface expression, however, and caveolin trafficking mutants sequester Kv1.5, but not Kv2.1, in intracellular compartments resulting in a loss of functional cell surface channel. Co-expression with wild type caveolin-1 does not alter Kv1.5 current density, but rather induces depolarizing shifts in steady-state activation and inactivation. These shifts are analogous to those produced by elevation of membrane cholesterol. Together, these results show that caveolin modulates channel function by regulating trafficking to cholesterol-rich membrane microdomains.


Key words: Ion channel regulation, Potassium, Lipid rafts/microdomains, Sequestration/Internalization, Immunocytochemistry


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R. Vicente, N. Villalonga, M. Calvo, A. Escalada, C. Solsona, C. Soler, M. M. Tamkun, and A. Felipe
Kv1.5 Association Modifies Kv1.3 Traffic and Membrane Localization
J. Biol. Chem., March 28, 2008; 283(13): 8756 - 8764.
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