Role of fibroblast growth factor homologous factors in excitability of hippocampal neurons
Item
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Title
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Role of fibroblast growth factor homologous factors in excitability of hippocampal neurons
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Identifier
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d_2009_2013:433f585ac76b:10069
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identifier
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10055
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Creator
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Huang, Xiao,
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Contributor
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Mitchell Goldfarb
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Date
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2009
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Language
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English
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Publisher
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City University of New York.
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Subject
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Neurosciences | electrophysiological recording | Fibroblast growth factor homologous factors | intrinsic excitability | real time PCR | RNAi | voltage-gated sodium channels
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Abstract
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Fibroblast growth factor homologous factors (FHFs) are a family of vertebrate neuronal proteins which function in manners distinct from fibroblast growth factors (FGFs). While bearing substantial sequence and structural homology to FGFs, FHFs reside intracellularly and bind targets unrelated to FGF receptors, which include voltage-gated sodium channels (Navs). FHFs have been shown to control excitability of cerebellar granule cells through modulation of channel inactivation. Since action potentials are initiated at axon initial segment (AIS), we suspected that at least some FHF isoforms would reside at AIS in association with Navs. As expected, a broad repertoire of FHF isoforms colocalizes with Navs at the AIS of cultured hippocampal neurons. Moreover, together with other studies in our laboratory, the present study shows that FHF "b" isoform associates with AIS to a far lesser extent than "a" isoform, demonstrating that there is isoform specificity in FHF targeting. AIS targeting of an FHF requires the protein's channel binding surface, as a mutant derivative of FHF2a deficient for channel binding is also deficient in AIS targeting.;The association of FHFs with Navs at AIS suggests that FHFs may modulate channel physiology, thereby controlling the intrinsic excitability of hippocampal neurons in a manner similar to that which has been described for cerebellar granule neurons of Fhf1-/-Fhf4 -/- mice. Moreover, real time PCR shows that FHF2 is the most abundant of the FHFs expressed in hippocampal neurons. The requirement of FHF2 for hippocampal neuron excitability was analyzed using RNAi in conjunction with electrophysiological recordings. These studies have demonstrated that knockdown of fhf2 in hippocampal neurons derived from Fhf1-/- mice impairs excitability, with less maximum spike frequency and elevated voltage thresholds for spike induction. Sodium channel inactivation parameters are altered in Fhf1-/-Fhf4 -/- granule neurons. In accordance, the colocalization and physical interaction of FHFs with Navs in hippocampal neurons suggest that excitability deficits could reflect altered channel physiology in cells lacking FHF1 and FHF2 function. These are the first data to indicate a role for FHF2 in neuronal excitability. These data suggest a widespread role for FHFs in the control of excitability across the central nervous system (CNS).
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
