An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels

Joel M. Brittain, Andrew D. Piekarz, Yuying Wang, Takako Kondo, Theodore R. Cummins, Rajesh Khanna

Research output: Contribution to journalArticle

136 Scopus citations

Abstract

Collapsin response mediator proteins (CRMPs) specify axon/dendrite fate and axonal growth of neurons through protein-protein interactions. Their functions in presynaptic biology remain unknown. Here, we identify the presynaptic N-type Ca2+ channel (CaV2.2) as a CRMP-2-interacting protein. CRMP-2 binds directly to CaV2.2 in two regions: the channel domain I-II intracellular loop and the distal C terminus. Both proteins co-localize within presynaptic sites in hippocampal neurons. Overexpression in hippocampal neurons of a CRMP-2 protein fused to enhanced green fluorescent protein caused a significant increase in Ca2+ channel current density, whereas lentivirus-mediated CRMP-2 knockdown abolished this effect. Interestingly, the increase in Ca2+ current density was not due to a change in channel gating. Rather, cell surface biotinylation studies showed an increased number of CaV2.2 at the cell surface in CRMP-2-overexpressing neurons. These neurons also exhibited a significant increase in vesicular release in response to a depolarizing stimulus. Depolarization of CRMP-2-enhanced green fluorescent protein-overexpressing neurons elicited a significant increase in release of glutamate compared with control neurons. Toxin block of Ca2+ entry via CaV2.2 abolished this stimulated release. Thus, the CRMP-2-Ca2+ channel interaction represents a novel mechanism for modulation of Ca2+ influx into nerve terminals and, hence, of synaptic strength.

Original languageEnglish (US)
Pages (from-to)31375-31390
Number of pages16
JournalJournal of Biological Chemistry
Volume284
Issue number45
DOIs
StatePublished - Nov 6 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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