The C-terminus of neuronal Kv2.1 channels is required for channel localization and targeting but not for NMDA-receptor-mediated regulation of channel function

The delayed rectifier voltage-gated potassium channel Kv2.1 underlies a majority of the somatic K+ current in neurons and is particularly important for regulating intrinsic neuronal excitability. Various stimuli alter Kv2.1 channel gating as well as localization of the channel to cell-surface cluster domains. It has been postulated that specific domains within the C-terminus of Kv2.1 are critical for channel gating and sub-cellular localization; however, the distinct regions that govern these processes remain elusive. Here we show that the soluble C-terminal fragment of the closely related channel Kv2.2 displaces Kv2.1 from clusters in both rat hippocampal neurons and HEK293 cells, however neither steady-state activity nor N-methyl-d-aspartate (NMDA)-dependent modulation is altered in spite of this non-clustered localization. Further, we demonstrate that the C-terminus of Kv2.1 is not necessary for steady-state gating, sensitivity to intracellular phosphatase or NMDA-dependent modulation, though this region is required for localization of Kv2.1 to clusters. Thus, the molecular determinants of Kv2.1 localization and modulation are distinct regions of the channel that function independently.

► Localization of Kv2.1 and Kv2.2 is governed by a common mechanism.
► Both NR2a- and NR2b-containing NMDA receptors modulate Kv2.1.
► The Kv2.2 C-terminus disrupts Kv2.1 clustering but not Kv2.1 gating.
► The C-terminus is required for clustering but not for gating or modulation of Kv2.1.