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Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells.
J Neurosci. 2014 Jul 02; 34(27):9107-23.JN

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 Ca(2+) 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 Ca(2+) entry (SOCE) mediated by Ca(2+) release-activated Ca(2+) (CRAC) channels. SOCE in NPCs was blocked by the CRAC channel inhibitors La(3+), 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 Ca(2+) signaling by Ca(2+) 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 Ca(2+) entry in NPCs and regulate key effector functions including gene expression and proliferation, indicating that CRAC channels are important regulators of mammalian neurogenesis.

Authors+Show Affiliations

Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.Department of Discovery Toxicology, Amgen, Inc., Thousand Oaks, California 91320.Department of Neurology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and.Department of Pathology, New York University Langone Medical Center, New York, New York 10016.Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, m-prakriya@northwestern.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24990931

Citation

Somasundaram, Agila, et al. "Store-operated CRAC Channels Regulate Gene Expression and Proliferation in Neural Progenitor Cells." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 34, no. 27, 2014, pp. 9107-23.
Somasundaram A, Shum AK, McBride HJ, et al. Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells. J Neurosci. 2014;34(27):9107-23.
Somasundaram, A., Shum, A. K., McBride, H. J., Kessler, J. A., Feske, S., Miller, R. J., & Prakriya, M. (2014). Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 34(27), 9107-23. https://doi.org/10.1523/JNEUROSCI.0263-14.2014
Somasundaram A, et al. Store-operated CRAC Channels Regulate Gene Expression and Proliferation in Neural Progenitor Cells. J Neurosci. 2014 Jul 2;34(27):9107-23. PubMed PMID: 24990931.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells. AU - Somasundaram,Agila, AU - Shum,Andrew K, AU - McBride,Helen J, AU - Kessler,John A, AU - Feske,Stefan, AU - Miller,Richard J, AU - Prakriya,Murali, PY - 2014/7/4/entrez PY - 2014/7/6/pubmed PY - 2014/8/30/medline KW - CRAC channels KW - Orai1 KW - STIM1 KW - calcium KW - progenitor cell KW - proliferation SP - 9107 EP - 23 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 34 IS - 27 N2 - 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 Ca(2+) 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 Ca(2+) entry (SOCE) mediated by Ca(2+) release-activated Ca(2+) (CRAC) channels. SOCE in NPCs was blocked by the CRAC channel inhibitors La(3+), 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 Ca(2+) signaling by Ca(2+) 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 Ca(2+) entry in NPCs and regulate key effector functions including gene expression and proliferation, indicating that CRAC channels are important regulators of mammalian neurogenesis. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/24990931/Store_operated_CRAC_channels_regulate_gene_expression_and_proliferation_in_neural_progenitor_cells_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=24990931 DB - PRIME DP - Unbound Medicine ER -