title: Fast-onset long-term open-state block of sodium channels by A-type FHFs mediates classical spike accommodation in hippocampal pyramidal neurons.
abstract: Classical accommodation is a form of spike frequency adaptation in neurons whereby excitatory drive results in action potential output of gradually decreasing frequency. Here we describe an essential molecular component underlying classical accommodation in juvenile mouse hippocampal CA1 pyramidal neurons. A-type isoforms of fibroblast growth factor homologous factors (FHFs) bound to axosomatic voltage-gated sodium channels bear an N-terminal blocking particle that drives some associated channels into a fast-onset, long-term inactivated state. Use-dependent accumulating channel blockade progressively elevates spike voltage threshold and lengthens interspike intervals. The FHF particle only blocks sodium channels from the open state, and mutagenesis studies demonstrate that this particle uses multiple aliphatic and cationic residues to both induce and maintain the long-term inactivated state. The broad expression of A-type FHFs in neurons throughout the vertebrate CNS suggests a widespread role of these sodium channel modulators in the control of neural firing.
authors.affiliation: Department of Biological Sciences, Hunter College of City University, New York, New York 10065 and.
authors.forename: Kumar
authors.identifier: http://orcid.org/0000-0001-5077-9380
authors.initials: K
authors.lastname: Venkatesan
authors.affiliation: Department of Biological Sciences, Hunter College of City University, New York, New York 10065 and The Graduate Center Neuroscience Training Subprogram at City University, New York, New York 10016.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biological Sciences, Hunter College of City University, New York, New York 10065 and Goldfarb@genectr.hunter.cuny.edu.
authors.forename: Mitchell
authors.identifier: http://orcid.org/0000-0002-7219-7645
authors.initials: M
authors.lastname: Goldfarb
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008969:Molecular Sequence Data; D017966:Pyramidal Cells / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology*; D013997:Time Factors
chemical_list: D015222:Sodium Channels; D005346:Fibroblast Growth Factors
keywords: A-type FHF; accommodation; hippocampus; long-term inactivation; open-state block; voltage gated sodium channel