Low voltage–activated potassium channels (Kv4) function at membrane potentials below those required to trigger an action potential to regulate overall neuronal excitability. Kv4 channels are composed of pore-forming subunits, a dipeptidylpeptidase-like protein, and a K+ channel–interaction protein (KChIP), which has calcium-binding domains and is proposed to confer calcium regulation to the Kv4 channels. Pharmacological experiments and calcium manipulation experiments combined with electrophysiology allowed Anderson et al. to show that primary cultures of stellate cells from rat cerebellum exhibited a Kv4-mediated current (IA) and that the voltage dependence of the inactivation of this current was set by T-type calcium channel activity. Coimmunoprecipitation experiments from rat brain demonstrated that Kv4, KChIP3, and T-type calcium channels (Cav3.2 or Cav3.3) interacted, and experiments with transfected cells showed that the interaction between the two types of channels required KChIP3. In transfected cells, the inhibitor of Cav3.3 only reduced Kv4 availability when KChIP3 was coexpressed. Disruption of KChIP function in cultured stellate cells by perfusion with antibodies reduced Kv4 availability and increased neuronal excitability. Thus, this two-channel and calcium sensor complex allows subthreshold calcium signals to set neuronal excitability.
D. Anderson, W. H. Mehaffey, M. Iftinca, R. Rehak, J. D. T. Engbers, S. Hameed, G. W. Zamponi, R. W. Turner, Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes. Nat. Neurosci. 13, 333–337 (2010). [PubMed]