Multiple Kv1.5 targeting to membrane surface microdomains

Abstract

Surface expression of voltage-dependent K + channels (Kv) has a pivotal role in leukocyte physiology. Although little is known about the physiological role of lipid rafts, these microdomains concentrate signaling molecules and their ion channel substrates. Kv1.3 associates with Kv1.5 to form functional channels in macrophages. Different isoform stoichiometries lead to distinct heteromeric channels which may be further modulated by targeting the complex to different membrane surface microdomains. Kv1.3 targets to lipid rafts, whereas Kv1.5 localization is under debate. With this in mind, we wanted to study whether heterotetrameric Kv1.5-containing channels target to lipid rafts. While in transfected HEK-293 cells, homo-and heterotetrameric channels targeted to rafts, Kv1.5 did not target to rafts in macrophages. Therefore, Kv1.3/Kv1.5 hybrid channels are mostly concentrated in non-raft microdomains. However, LPS-induced activation, which increases the Kv1.3/Kv1.5 ratio and caveolin, targeted Kv1.5 back to lipid rafts. Moreover, Kv1.5 did not localize to low-buoyancy fractions in L6E9 skeletal myoblasts, which also coexpress both channels, heart membranes or cardiomyocyes. Coexpression of a Cav3 DGVmutant confined Kv1.5 to Cav3 DGV -vesicles of HEK cells. Contrarily, coexpression of Kvβ2.1 impaired the Kv1.5 targeting to raft microdomains in HEK cells. Our results indicate that Kv1.5 partnership interactions are underlying mechanisms governing channel targeting to lipid rafts.

α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac KV4 channels

“…Thus, K V 1.5 channels do not appear in membrane rafts when expressed alone, but are directed to membrane rafts when coexpressed with K V 1.3 channels. 25 Similarly, PSD95 increases the raft association of K V 1.4 channels. 14 In this sense, the K V 4.3 channel protein has a consensus sequence for interaction with caveolin (ΦXXXXΦXXΦ, aminoacids 165-173 of K V 4.3) and K V 4.2 lacks this sequence.…”

KCNE4 suppresses Kv1.3 currents by modulating trafficking, surface expression and channel gating

“…However, scaffolding proteins, such as membrane associated guanylate kinases (MAGUK) and caveolins, improve Kv1.5 channel association with raft domains (Folco et al, 2004). Unlike scaffolding proteins, Kv2.1 regulatory subunit mistargets Kv1.5 channels to lipid rafts (Martinez-Marmol et al, 2008). Similarly, KCNE4 act as a repressor ancillary subunit.…”

“…However, Kv1.3 targeting is impaired by oligomerization with Kv1.5 (Martinez-Marmol et al, 2008;Vicente et al, 2008). In addition, the association of Kv1.5 with the Kv2.1 regulatory subunit impairs channel targeting to rafts (Martinez-Marmol et al, 2008). With this in mind, we analyzed whether KCNE4 modifies Kv1.3 targeting to these domains.…”

“…In this context, Kv1.3 is targeted to raft domains involved in immunological synapses in T-cells (Panyi et al, 2004b), but the association of Kv1.3 and Kv1.5 in macrophages alters trafficking and targeting. However, pro-inflammatory activation targets Kv1.3 back to lipid rafts (Martinez-Marmol et al, 2008;Vicente et al, 2008). These determinants affect the expression and functional properties of the channels and contribute to the diversity of K + channels in leukocytes.…”

Plasticity in Membrane Cholesterol Contributes toward Electrical Maturation of Hearing

“…Alternatively, it is conceivable that cholesterol modulates the surface distribution of the channels, which, as it turns out, has marked impact on channel functions (31,42). Furthermore, in addition to direct interactions with membrane cholesterol, the observed potentiation of I Kv in developing hair cells could ensue from indirect association of K v channels with other binding proteins that are lipid-sensitive (33,43,44). Moreover, cholesterol depletion eliminates SAPs in developing hair cells, and in keeping with the roles of K v channels, the resting membrane potential and action potential durations were altered accordingly.…”