title: Auxiliary KChIP4a suppresses A-type K+ current through endoplasmic reticulum (ER) retention and promoting closed-state inactivation of Kv4 channels.
abstract: In the brain and heart, auxiliary Kv channel-interacting proteins (KChIPs) co-assemble with pore-forming Kv4 α-subunits to form a native K(+) channel complex and regulate the expression and gating properties of Kv4 currents. Among the KChIP1-4 members, KChIP4a exhibits a unique N terminus that is known to suppress Kv4 function, but the underlying mechanism of Kv4 inhibition remains unknown. Using a combination of confocal imaging, surface biotinylation, and electrophysiological recordings, we identified a novel endoplasmic reticulum (ER) retention motif, consisting of six hydrophobic and aliphatic residues, 12-17 (LIVIVL), within the KChIP4a N-terminal KID, that functions to reduce surface expression of Kv4-KChIP complexes. This ER retention capacity is transferable and depends on its flanking location. In addition, adjacent to the ER retention motif, the residues 19-21 (VKL motif) directly promote closed-state inactivation of Kv4.3, thus leading to an inhibition of channel current. Taken together, our findings demonstrate that KChIP4a suppresses A-type Kv4 current via ER retention and enhancement of Kv4 closed-state inactivation.
authors.affiliation: Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Peking University School of Pharmaceutical Sciences, Beijing 100191, China.
authors.forename: Yi-Quan
authors.initials: YQ
authors.lastname: Tang
authors.forename: Ping
authors.initials: P
authors.lastname: Liang
authors.forename: Jingheng
authors.initials: J
authors.lastname: Zhou
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Lu
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.forename: Xiling
authors.initials: X
authors.lastname: Bian
authors.forename: KeWei
authors.initials: K
authors.lastname: Wang
mesh_terms: D020816:Amino Acid Motifs; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport / Q000502:physiology; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051605:Kv Channel-Interacting Proteins; D051672:Shal Potassium Channels; D011188:Potassium
keywords: Closed-state Inactivation; Confocal Microscopy; Electrophysiology; Endoplasmic Reticulum (ER); Gating; KChIPs; Kv4; Neurobiology; Potassium Channels; Trafficking