Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells

Agila Somasundaram, Andrew K. Shum, Helen J. McBride, John A. Kessler, Stefan Feske, Richard J. Miller, Murali Prakriya*

*Corresponding author for this work

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Calcium signals regulate many critical processes during vertebrate brain development including neurogenesis, neurotransmitter specification, and axonal outgrowth. However, the identity of the ion channels mediating Ca2+ signaling in the developing nervous system is not well defined. Here, we report that embryonic and adult mouse neural stem/progenitor cells (NSCs/NPCs) exhibit store-operated Ca2+ entry (SOCE) mediated by Ca2+ release-activated Ca2+ (CRAC) channels. SOCE in NPCs was blocked by the CRAC channel inhibitors La3+, BTP2, and 2-APB and Western blots revealed the presence of the canonical CRAC channel proteins STIM1 and Orai1. Knock down of STIM1 or Orai1 significantly diminished SOCE in NPCs, and SOCE was lost in NPCs from transgenic mice lacking Orai1 or STIM1 and in knock-in mice expressing the loss-of-function Orai1 mutant, R93W. Therefore, STIM1 and Orai1 make essential contributions to SOCE in NPCs. SOCE in NPCs was activated by epidermal growth factor and acetylcholine, the latter occurring through muscarinic receptors. Activation of SOCE stimulated gene transcription through calcineurin/NFAT (nuclear factor of activated T cells) signaling through a mechanism consistent with local Ca2+ signaling by Ca2+ microdomains near CRAC channels. Importantly, suppression or deletion of STIM1 and Orai1 expression significantly attenuated proliferation of embryonic and adult NPCs cultured as neurospheres and, in vivo, in the subventricular zone of adult mice. These findings show that CRAC channels serve as a major route of Ca2+entry in NPCs and regulate key effector functions including gene expression and proliferation, indicating that CRAC channels are important regulators of mammalian neurogenesis.

Original languageEnglish (US)
Pages (from-to)9107-9123
Number of pages17
JournalJournal of Neuroscience
Volume34
Issue number27
DOIs
StatePublished - 2014

Keywords

  • CRAC channels
  • Calcium
  • Orai1
  • Progenitor cell
  • Proliferation
  • STIM1

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells'. Together they form a unique fingerprint.

  • Cite this