Analysis of mutant platelet-derived growth factor receptors expressed in PC12 cells identifies signals governing sodium channel induction during neuronal differentiation

Gary R. Fanger, Richard R. Vaillancourt, Lynn E. Heasley, Jean Pierre R. Montmayeur, Gary L. Johnson, Robert A. Maue

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The mechanisms governing neuronal differentiation, including the signals underlying the induction of voltage-dependent sodium (Na+) channel expression by neurotrophic factors, which occurs independent of Ras activity, are not well understood. Therefore, Na+ channel induction was analyzed in sublines of PC12 cells stably expressing platelet-derived growth factor (PDGF) β receptors with mutations that eliminate activation of specific signaling molecules. Mutations eliminating activation of phosphatidylinositol 3-kinase (PI3K), phospholipase C(γ) (PLC(γ)), the GTPase-activating protein (GAP), and Syp phosphatase failed to diminish the induction of type II Na+ channel α-subunit mRNA and functional Na+ channel expression by PDGF, as determined by RNase protection assays and whole-cell patch clamp recording. However, mutation of juxtamembrane tyrosines that bind members of the Src family of kinases upon receptor activation inhibited the induction of functional Na+ channels while leaving the induction of type II α-subunit mRNA intact. Mutation of juxtamembrane tyrosines in combination with mutations eliminating activation of PI3K, PLC(γ), GAP, and Syp abolished the induction of type II α-subunit mRNA, suggesting that at least partially redundant signaling mechanisms mediate this induction. The differential effects of the receptor mutations on Na+ channel expression did not reflect global changes in receptor signaling capabilities, as in all of the mutant receptors analyzed, the induction of c-fos and transin mRNAs still occurred. The results reveal an important role for the Src family in the induction of Na+ channel expression and highlight the multiplicity and combinatorial nature of the signaling mechanisms governing neuronal differentiation.

Original languageEnglish (US)
Pages (from-to)89-99
Number of pages11
JournalMolecular and cellular biology
Volume17
Issue number1
DOIs
StatePublished - Jan 1997
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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