Regulation of Nav1.6 and Nav1.8 peripheral nerve Na+ channels by auxiliary β-subunits

Juan Zhao, Michael E. O'Leary, Mohamed Chahine

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37 Scopus citations

Abstract

Regulation of Nav1.6 and Nav1.8 peripheral nerve Na+ channels by auxiliary β-subunits. J Neurophysiol 106: 608-619, 2011. First published May 11, 2011; doi:10.1152/jn.00107.2011-Voltage-gated Na+ (Nav) channels are composed of a pore-forming -subunit and one or more auxiliary β-subunits. The present study investigated the regulation by the β-subunit of two Na+ channels (Nav1.6 and Nav1.8) expressed in dorsal root ganglion (DRG) neurons. Single cell RT-PCR was used to show that Nav1.8, Nav1.6, and β13 subunits were widely expressed in individually harvested small-diameter DRG neurons. Coexpression experiments were used to assess the regulation of Nav1.6 and Nav1.8 by β-subunits. The β1-subunit induced a 2.3-fold increase in Na+ current density and hyperpolarizing shifts in the activation (β4 mV) and steady-state inactivation (-4.7 mV) of heterologously expressed Nav1.8 channels. The β4-subunit caused more pronounced shifts in activation (-16.7 mV) and inactivation (-9.3 mV) but did not alter the current density of cells expressing Nav1.8 channels. The β3-subunit did not alter Nav1.8 gating but significantly reduced the current density by 31%. This contrasted with Nav1.6, where the β-subunits were relatively weak regulators of channel function. One notable exception was the β4-subunit, which induced a hyperpolarizing shift in activation (-7.6 mV) but no change in the inactivation or current density of Nav1.6. The β-subunits differentially regulated the expression and gating of Nav1.8 and Nav1.6. To further investigate the underlying regulatory mechanism, β-subunit chimeras containing portions of the strongly regulating β1-subunit and the weakly regulating β2-subunit were generated. Chimeras retaining the COOH-terminal domain of the β1-subunit produced hyperpolarizing shifts in gating and increased the current density of Nav1.8, similar to that observed for wild-type β1-subunits. The intracellular COOH-terminal domain of the β1-subunit appeared to play an essential role in the regulation of Nav1.8 expression and gating.

Original languageEnglish (US)
Pages (from-to)608-619
Number of pages12
JournalJournal of Neurophysiology
Volume106
Issue number2
DOIs
StatePublished - Aug 2011

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Physiology

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