KCNE4 suppresses Kv1.3 currents by modulating trafficking, surface expression and channel gating.
Voltage-dependent potassium channels (Kv) play a crucial role in the activation and proliferation of leukocytes. Kv channels are either homo- or hetero-oligomers. This composition modulates their surface expression and serves as a mechanism for regulating channel activity. Kv channel interaction with accessory subunits provides mechanisms for channels to respond to stimuli beyond changes in membrane potential. Here, we demonstrate that KCNE4 (potassium voltage-gated channel subfamily E member 4), but not KCNE2, functions as an inhibitory Kv1.3 partner in leukocytes. Kv1.3 trafficking, targeting and activity are altered by the presence of KCNE4. KCNE4 decreases current density, slows activation, accelerates inactivation, increases cumulative inactivation, retains Kv1.3 in the ER and impairs channel targeting to lipid raft microdomains. KCNE4 associates with Kv1.3 in the ER and decreases the number of Kv1.3 channels at the cell surface, which diminishes cell excitability. Kv1.3 and KCNE4 are differentially regulated upon activation or immunosuppression in macrophages. Thus, lipopolysaccharide-induced activation increases Kv1.3 and KCNE4 mRNA, whereas dexamethasone triggers a decrease in Kv1.3 with no changes in KCNE4. The channelosome composition determines the activity and affects surface expression and membrane localization. Therefore, KCNE4 association might play a crucial role in controlling immunological responses. Our results indicate that KCNE ancillary subunits could be new targets for immunomodulation.
Departament de Bioquímica i Biologia Molecular, Molecular Physiology Laboratory, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda. Diagonal 645, 08028 Barcelona, Spain.
Laura
L
Solé
Meritxell
M
Roura-Ferrer
Mireia
M
Pérez-Verdaguer
Anna
A
Oliveras
Maria
M
Calvo
José Manuel
JM
Fernández-Fernández
Antonio
A
Felipe
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D036681:Fluorescence Recovery After Photobleaching; D005786:Gene Expression Regulation; D006801:Humans; D015640:Ion Channel Gating; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
C498897:KCNE4 protein, human; C470587:KCNE4 protein, mouse; D051664:Kv1.3 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger