Caveolin regulates kv1.5 trafficking to cholesterol-rich membrane microdomains.
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 -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.
Department of Pharmacology, University of Michigan, 1150 W. Medical Center Drive, 1301 MSRB III, Ann Arbor, MI 48109-5632, USA.
Dyke P
DP
McEwen
Qiuju
Q
Li
Sajida
S
Jackson
Paul M
PM
Jenkins
Jeffrey R
JR
Martens
D000818:Animals; D051242:Caveolin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051244:Caveolin 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D022461:Caveolins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D018076:DNA, Complementary; D004594:Electrophysiology; D005260:Female; D007150:Immunohistochemistry; D051666:Kv1.5 Potassium Channel / Q000378:metabolism*; D021962:Membrane Microdomains / Q000737:chemistry*; D009154:Mutation; D018408:Patch-Clamp Techniques; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D051242:Caveolin 1; D051244:Caveolin 3; D022461:Caveolins; D018076:DNA, Complementary; D051666:Kv1.5 Potassium Channel; D011993:Recombinant Fusion Proteins; D002784:Cholesterol