Spontaneous glutamate release is independent of calcium influx and tonically activated by the calcium-sensing receptor

Nicholas P. Vyleta, Stephen M. Smith

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Spontaneous release of glutamate is important for maintaining synaptic strength and controlling spike timing in the brain. Mechanisms regulating spontaneous exocytosis remain poorly understood. Extracellular calcium concentration ([Ca2+]o) regulates Ca2+ entry through voltage-activated calcium channels (VACCs) and consequently is a pivotal determinant of action potential-evoked vesicle fusion. Extracellular Ca 2+ also enhances spontaneous release, but via unknown mechanisms. Here we report that external Ca2+ triggers spontaneous glutamate release more weakly than evoked release in mouse neocortical neurons. Blockade of VACCs has no effect on the spontaneous release rate or its dependence on [Ca2+]o. Intracellular [Ca2+] slowly increases in a minority of neurons following increases in [Ca2+]o. Furthermore, the enhancement of spontaneous release by extracellular calcium is insensitive to chelation of intracellular calcium by BAPTA. Activation of the calcium-sensing receptor (CaSR), a G-protein-coupled receptor present in nerve terminals, by several specific agonists increased spontaneous glutamate release. The frequency of spontaneous synaptic transmission was decreased in CaSR mutant neurons. The concentration-effect relationship for extracellular calcium regulation of spontaneous release was well described by a combination of CaSR-dependent and CaSR-independent mechanisms. Overall these results indicate that extracellular Ca2+ does not trigger spontaneous glutamate release by simply increasing calcium influx but stimulates CaSR and thereby promotes resting spontaneous glutamate release.

Original languageEnglish (US)
Pages (from-to)4593-4606
Number of pages14
JournalJournal of Neuroscience
Volume31
Issue number12
DOIs
StatePublished - Mar 23 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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