The Kv2.1 C terminus can autonomously transfer Kv2.1-like phosphorylation-dependent localization, voltage-dependent gating, and muscarinic modulation to diverse Kv channels

Durga P. Mohapatra, James Trimmer

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Modulation of K+ channels is widely used to dynamically regulate neuronal membrane excitability. The voltage-gated K+ channel Kv2.1 is an abundant delayed rectifier K+ (IK) channel expressed at high levels in many types of mammalian central neurons where it regulates diverse aspects of membrane excitability. Neuronal Kv2.1 is constitutively phosphorylated, localized in high-density somatodendritic clusters, and has a relatively depolarized voltage dependence of activation. Here, we show that the clustering and voltage-dependent gating of endogenous Kv2.1 in cultured rat hippocampal neurons are modulated by cholinergic stimulation, a common form of neuromodulation. The properties of neuronal Kv2.1 are recapitulated in recombinant Kv2.1 expressed in human embryonic kidney 293 (HEK293) cells, but not COS-1 cells, because of cell background-specific differences in Kv2.1 phosphorylation. As in neurons, Kv2.1 in HEK293 cells is dynamically regulated by cholinergic stimulation, which leads to Ca2+/calcineurin-dependent dephosphorylation of Kv2.1, dispersion of channel clusters, and hyperpolarizing shifts in the voltage-dependent gating properties of the channel. Immunocytochemical, biochemical, and biophysical analyses of chimeric Kv channels show that the Kv2.1 cytoplasmic C-terminal domain can act as an autonomous domain sufficient to transfer Kv2.1-like clustering, voltage-dependent activation, and cholinergic modulation to diverse Kv channels. These findings provide novel mechanistic insights into cholinergic modulation of ion channels and regulation of the localization and voltage-dependent gating properties of the abundant neuronal Kv2.1 channel by cholinergic and other neuromodulatory stimuli.

Original languageEnglish (US)
Pages (from-to)685-695
Number of pages11
JournalJournal of Neuroscience
Volume26
Issue number2
DOIs
StatePublished - Jan 11 2006

Keywords

  • Acetylcholine
  • Calcineurin
  • Calcium
  • Hippocampus
  • Intracellular signaling
  • Kv2.1
  • Neuromodulation

ASJC Scopus subject areas

  • Neuroscience(all)

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