Isoform-specific localization of voltage-gated K+ channels to distinct lipid raft populations - Targeting of Kv1.5 to 3 caveolae

The precise subcellular localization of ion channels is often necessary to ensure rapid and efficient integration of both intracellular and extracellu lar signaling events. Recently, we have identified lipid raft association a s a novel mechanism for the subcellular sorting of specific voltage gated K + channels to regions of the membrane rich in signaling complexes. Here, we demonstrate isoform-specific targeting of voltage-gated KC (Kv) channels t o distinct lipid raft populations with the finding that Kv1.5 specifically targets to caveolae. Multiple lines of evidence indicate that Kv1.5 and Kv2 .1 exist in distinct raft domains: 1) channel/raft association shows differ ential sensitivity to increasing concentrations of Triton X-100; 2) unlike Kv2.1, Kv1.5 colocalizes with caveolin on the cell surface and redistribute s with caveolin following microtubule disruption; and 3) immunoisolation of caveolae copurifies Kv1.5 channel. Both depletion of cellular cholesterol and inhibition of sphingolipid synthesis alter Kv1.5 channel function by in ducing a hyperpolarizing shift in the voltage dependence of activation and inactivation. The differential targeting of Kv channel subtypes to caveolar and noncaveolar rafts within a single membrane represents a unique mechani sm of compartmentalization, which may permit isoform-specific modulation of K+ channel function.