title: Interdomain cytoplasmic interactions govern the intracellular trafficking, gating, and modulation of the Kv2.1 channel.
abstract: Voltage-gated potassium (Kv) channels comprise four transmembrane alpha subunits, often associated with cytoplasmic beta subunits that impact channel expression and function. Here, we show that cell surface expression, voltage-dependent activation gating, and phosphorylation-dependent modulation of Kv2.1 are regulated by cytoplasmic N/C interaction within the alpha subunit. Kv2.1 surface expression is greatly reduced by C-terminal truncation. Tailless Kv2.1 channels exhibit altered voltage-dependent gating properties and lack the bulk of the phosphorylation-dependent modulation of channel gating. Remarkably, the soluble C terminus of Kv2.1 associates with tailless channels and rescues their expression, function, and phosphorylation-dependent modulation. Soluble N and C termini of Kv2.1 can also interact directly. We also show that the N/C-terminal interaction in Kv2.1 is governed by a 34 aa motif in the juxtamembrane cytoplasmic C terminus, and a 17 aa motif located in the N terminus at a position equivalent to the beta subunit binding site in other Kv channels. Deletion of either motif disrupts N/C-terminal interaction and surface expression, function, and phosphorylation-dependent modulation of Kv2.1 channels. These findings provide novel insights into intrinsic mechanisms for the regulation of Kv2.1 trafficking, gating, and phosphorylation-dependent modulation through cytoplasmic N/C-terminal interaction, which resembles alpha/beta subunit interaction in other Kv channels.
authors.affiliation: Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, California 95616, USA.
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
authors.forename: Dominic F
authors.initials: DF
authors.lastname: Siino
authors.forename: James S
authors.initials: JS
authors.lastname: Trimmer
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism*; D004594:Electrophysiology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D009154:Mutation / Q000502:physiology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D051669:Shab Potassium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D051669:Shab Potassium Channels