Action potential generation is governed by the opening, inactivation, and recovery of voltage-gated sodium channels. A channel's voltage-sensing and pore-forming alpha subunit bears an intrinsic fast inactivation particle that mediates both onset of inactivation upon membrane depolarization and rapid recovery upon repolarization. We describe here a novel inactivation particle housed within an accessory channel subunit (A-type FHF protein) that mediates rapid-onset, long-term inactivation of several sodium channels. The channel-intrinsic and tethered FHF-derived particles, both situated at the cytoplasmic face of the plasma membrane, compete for induction of inactivation, causing channels to progressively accumulate into the long-term refractory state during multiple cycles of membrane depolarization. Intracellular injection of a short peptide corresponding to the FHF particle can reproduce channel long-term inactivation in a dose-dependent manner and can inhibit repetitive firing of cerebellar granule neurons. We discuss potential structural mechanisms of long-term inactivation and potential roles of A-type FHFs in the modulation of action potential generation and conduction

Long-term inactivation particle for voltage-gated sodium channels / Dover, K; Solinas, S; D'Angelo, E; Goldfarb, M.. - In: THE JOURNAL OF PHYSIOLOGY. - ISSN 0022-3751. - 588:19(2010), pp. 3695-3711. [10.1113/jphysiol.2010.192559]

Long-term inactivation particle for voltage-gated sodium channels

Solinas S
Investigation
;
2010

Abstract

Action potential generation is governed by the opening, inactivation, and recovery of voltage-gated sodium channels. A channel's voltage-sensing and pore-forming alpha subunit bears an intrinsic fast inactivation particle that mediates both onset of inactivation upon membrane depolarization and rapid recovery upon repolarization. We describe here a novel inactivation particle housed within an accessory channel subunit (A-type FHF protein) that mediates rapid-onset, long-term inactivation of several sodium channels. The channel-intrinsic and tethered FHF-derived particles, both situated at the cytoplasmic face of the plasma membrane, compete for induction of inactivation, causing channels to progressively accumulate into the long-term refractory state during multiple cycles of membrane depolarization. Intracellular injection of a short peptide corresponding to the FHF particle can reproduce channel long-term inactivation in a dose-dependent manner and can inhibit repetitive firing of cerebellar granule neurons. We discuss potential structural mechanisms of long-term inactivation and potential roles of A-type FHFs in the modulation of action potential generation and conduction
Long-term inactivation particle for voltage-gated sodium channels / Dover, K; Solinas, S; D'Angelo, E; Goldfarb, M.. - In: THE JOURNAL OF PHYSIOLOGY. - ISSN 0022-3751. - 588:19(2010), pp. 3695-3711. [10.1113/jphysiol.2010.192559]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11388/239222
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