5-Hydroxytryptamine 5HT2C receptors form a protein complex with N-methyl-D-aspartate GluN2A subunits and activate phosphorylation of Src protein to modulate motoneuronal depolarization

Gregory E. Bigford, Nauman S. Chaudhry, Robert W. Keane, Alice M. Holohean

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

N-Methyl-D-aspartate (NMDA)-gated ion channels are known to play a critical role in motoneuron depolarization, but the molecular mechanisms modulating NMDA activation in the spinal cord are not well understood. This study demonstrates that activated 5HT2C receptors enhance NMDA depolarizations recorded electrophysiologically from motoneurons. Pharmacological studies indicate involvement of Src tyrosine kinase mediates 5HT2C facilitation of NMDA. RT-PCR analysis revealed edited forms of 5HT2C were present in mammalian spinal cord, indicating the availability of G-protein-independent isoforms. Spinal cord neurons treated with the 5HT2C agonist MK 212 showed increased SrcTyr-416 phosphorylation in a dose-dependent manner thus verifying that Src is activated after treatment. In addition, 5HT2C antagonists and tyrosine kinase inhibitors blocked 5HT2C-mediated SrcTyr-416 phosphorylation and also enhanced NMDA-induced motoneuron depolarization. Co-immunoprecipitation of synaptosomal fractions showed that GluN2A, 5HT2C receptors, and Src tyrosine kinase form protein associations in synaptosomes. Moreover, immunohistochemical analysis demonstrated GluN2A and 5HT2C receptors co-localize on the processes of spinal neurons. These findings reveal that a distinct multiprotein complex links 5-hydroxytryptamine-activated intracellular signaling events with NMDA-mediated functional activity.

Original languageEnglish (US)
Pages (from-to)11049-11059
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number14
DOIs
StatePublished - Mar 30 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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