GABAA and GABAB receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+

Marija Schwirtlich, Z. Emri, K. Antal, Zoltán Máté, Zoya Katarova, Gábor Szabó

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Gamma-amminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system of vertebrates, serves as an autocrine/paracrine signaling molecule during development, modulating a number of calcium (Ca 2+)-dependent processes, including proliferation, migration, and differentiation, acting via 2 types of GABA receptors (GABARs): ionotropic GABAARs and metabotropic GABABRs. Here, we demonstrate that mouse embryonic stem cells (mESCs), which possess the capacity for virtually unlimited self-renewal and pluripotency, synthesize GABA and express functional GABAARs and GABABRs, as well as voltage-gated calcium channels (VGCCs), ryanodine receptors (RyRs), and inwardly rectifying potassium (GIRK) channels. On activation, both GABAR types triggered synergistically intracellular calcium rise. Muscimol (a GABAAR agonist) induced single Ca2+ transients involving both VGCC-mediated Ca2+ influx and intracellular stores, while baclofen (a GABA BR agonist) evoked Ca2+ transients followed by intercellular Ca2+ waves and oscillations that were resistant to antagonists and entirely dependent on Ca2+ release from intracellular stores. Prolonged treatment with muscimol slightly inhibited, while baclofen or SR95531 (a GABAAR antagonist) significantly facilitated, mESC proliferation. GABAAR-specific ligands also induced morphological and gene expression changes indicating a differentiation shift. Our data suggest that the interplay between GABARs and downstream (coupled) effectors differentially modulates mESC proliferation/differentiation through selective activation of second messenger signaling cascades.

Original languageEnglish
Pages (from-to)1218-1228
Number of pages11
JournalFASEB Journal
Volume24
Issue number4
DOIs
Publication statusPublished - Apr 2010

Fingerprint

GABA-A Receptors
Stem cells
Muscimol
Baclofen
Acids
GABA Receptors
Cell proliferation
Calcium Channels
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Chemical activation
Autocrine Communication
Cell Proliferation
Paracrine Communication
Inwardly Rectifying Potassium Channel
Calcium
Ryanodine Receptor Calcium Release Channel
Neurology
Electric potential
Second Messenger Systems
Gene expression

Keywords

  • Ca imaging
  • Connexin 43
  • ES cell self-renewal/differentiation

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

GABAA and GABAB receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+. / Schwirtlich, Marija; Emri, Z.; Antal, K.; Máté, Zoltán; Katarova, Zoya; Szabó, Gábor.

In: FASEB Journal, Vol. 24, No. 4, 04.2010, p. 1218-1228.

Research output: Contribution to journalArticle

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