Growth factor receptor tyrosine kinases acutely regulate neuronal sodium channels through the Src signaling pathway

Michael D. Hilborn, Richard Vaillancourt, Stanley G. Rane

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Growth factor receptor tyrosine kinase (RTK)-activated signaling pathways are well established regulators of neuronal growth and development, but whether these signals provide mechanisms for acute modulation of neuronal activity is just beginning to be addressed. We show in pheochromocytoma (PC12) cells that acute application of ligands for both endogenous RTKs [trkA, basic FGF (bFGF) receptor, and epidermal growth factor (EGF) receptor] and ectopically expressed platelet-derived growth factor (PDGF) receptors rapidly inhibits whole-cell sodium channel currents, coincident with a hyperpolarizing shift in the voltage dependence of inactivation. Sodium channel inhibition by trkA and PDGF receptors is mutually occlusive, suggestive of a common signal transduction mechanism. Furthermore, specific inhibitors for trkA and PDGF RTK activities abrogate sodium channel inhibition in response to NGF and PDGF, respectively, showing that the intrinsic RTK activity of these receptors is necessary for sodium channel inhibition. Use of PDGF receptor mutants deficient for specific signaling activities demonstrated that this inhibition is dependent on RTK interaction with Src but not with other RTK-associated signaling molecules. Inhibition was also compromised in cells expressing dominant-negative Ras. These results suggest a possible mechanism for acute physiological actions of RTKs, and they indicate regulatory functions for Ras and Src that may complement the roles of these signaling proteins in long-term neuronal regulation.

Original languageEnglish (US)
Pages (from-to)590-600
Number of pages11
JournalJournal of Neuroscience
Volume18
Issue number2
Publication statusPublished - 1998

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Keywords

  • Growth factor receptor tyrosine kinases
  • NGF
  • PC12 cells
  • PDGF receptors
  • Ras
  • Sodium channels
  • Src

ASJC Scopus subject areas

  • Neuroscience(all)

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