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

• Published in: Molecular pharmacology Vol. 73; no. 3; pp. 678 - 685
• Main Authors: McEwen, Dyke P, Li, Qiuju, Jackson, Sajida, Jenkins, Paul M, Martens, Jeffrey R
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.03.2008
• Subjects: Animals; Caveolin 1 - chemistry; Caveolin 1 - genetics; Caveolin 1 - metabolism; Caveolin 3 - chemistry; Caveolin 3 - genetics; Caveolin 3 - metabolism; Caveolins - genetics; Caveolins - metabolism; Caveolins - physiology; Cell Line; Cholesterol - metabolism; DNA, Complementary; Electrophysiology; Female; Immunohistochemistry; Kv1.5 Potassium Channel - metabolism; Membrane Microdomains - chemistry; Mutation; Patch-Clamp Techniques; Protein Transport; Rats; Recombinant Fusion Proteins - metabolism
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.107.042093

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 α-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 -3, the association of Kv1.5 with low-density, detergent-resistant membrane fractions requires coexpression 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. Coexpression with wild type caveolin-1 does not alter Kv1.5 current density; rather, it 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.