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The Journal of Neuroscience, January 11, 2006, 26(2):685-695; doi:10.1523/JNEUROSCI.4620-05.2006

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Cellular/Molecular
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 and James S. Trimmer

Department of Pharmacology, School of Medicine, University of California, Davis, California 95616

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⁺ (I_K) 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.

Key words: Kv2.1; calcineurin; neuromodulation; acetylcholine; hippocampus; intracellular signaling; calcium

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Received Oct 27, 2005; revised December 1, 2005; accepted December 5, 2005.

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