title: Alternative splicing regulates kv3.1 polarized targeting to adjust maximal spiking frequency.
abstract: Synaptic inputs received at dendrites are converted into digital outputs encoded by action potentials generated at the axon initial segment in most neurons. Here, we report that alternative splicing regulates polarized targeting of Kv3.1 voltage-gated potassium (Kv) channels to adjust the input-output relationship. The spiking frequency of cultured hippocampal neurons correlated with the level of endogenous Kv3 channels. Expression of axonal Kv3.1b, the longer form of Kv3.1 splice variants, effectively converted slow-spiking young neurons to fast-spiking ones; this was not the case for Kv1.2 or Kv4.2 channel constructs. Despite having identical biophysical properties as Kv3.1b, dendritic Kv3.1a was significantly less effective at increasing the maximal firing frequency. This suggests a possible role of channel targeting in regulating spiking frequency. Mutagenesis studies suggest the electrostatic repulsion between the Kv3.1b N/C termini, created by its C-terminal splice domain, unmasks the Kv3.1b axonal targeting motif. Kv3.1b axonal targeting increased the maximal spiking frequency in response to prolonged depolarization. This finding was further supported by the results of local application of channel blockers and computer simulations. Taken together, our studies have demonstrated that alternative splicing controls neuronal firing rates by regulating the polarized targeting of Kv3.1 channels.
authors: Department of Neuroscience and Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, USA. gu.49@osu.edu
authors: Yuanzheng
authors: Y
authors: Gu
authors: Joshua
authors: J
authors: Barry
authors: Robert
authors: R
authors: McDougel
authors: David
authors: D
authors: Terman
authors: Chen
authors: C
authors: Gu
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D051670:Shaw Potassium Channels / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D051670:Shaw Potassium Channels