Molecular determinants for modulation of persistent sodium current by G-protein βγ subunits

Massimo Mantegazza, Frank H. Yu, Andrew J. Powell, Jeffrey J. Clare, William A. Catterall, Todd Scheuer

Research output: Contribution to journalArticlepeer-review

Abstract

Voltage-gated sodium channels are responsible for the upstroke of the action potential in most excitable cells, and their fast inactivation is essential for controlling electrical signaling. In addition, a noninactivating, persistent component of sodium current, INaP, has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein βγ subunits increase INaP, but the sodium channel subtypes that conduct INaP and the target site(s) on the sodium channel molecule required for modulation by Gβγ are poorly defined. Here, we show that INaP conducted by Nav1.1 and Nav1.2 channels (Nav1.1 > Nav1.2) is modulated by Gβγ; Nav1.4 and Na v1.5 channels produce smaller INaP that is not regulated by Gβγ. These qualitative differences in modulation by Gβγ are determined by the transmembrane body of the sodium channels rather than their cytoplasmic C-terminal domains, which have been implicated previously in modulation by Gβγ. However, the C-terminal domains determine the quantitative extent of modulation of Nav1.2 channels by Gβγ. Studies of chimeric and truncated Nav1.2 channels identify molecular determinants that affect modulation of INaP located between amino acid residue 1890 and the C terminus at residue 2005. The last 28 amino acid residues of the C terminus are sufficient to support modulation by Gβγ when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generate I Nap and identify crucial molecular determinants in the C-terminal domain required for modulation by Gβγ when attached to the transmembrane body of a responsive sodium channel.

Original languageEnglish
Pages (from-to)3341-3349
Number of pages9
JournalJournal of Neuroscience
Volume25
Issue number13
DOIs
Publication statusPublished - Mar 30 2005

Keywords

  • Channels
  • Excitability
  • G-proteins
  • Inactivation
  • Neuromodulation
  • Sodium

ASJC Scopus subject areas

  • Neuroscience(all)

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