Role of regulator of G protein signaling 2 (RGS2) in Ca2+ oscillations and adaptation of Ca2+ signaling to reduce excitability of RGS2-/- cells

Xinhua Wang, Guojin Huang, Xiang Luo, Josef M. Penninger, Shmuel Muallem

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Regulators of G protein signaling (RGS) proteins accelerate the GTPase activity of Gα subunits to determine the duration of the stimulated state and control G protein-coupled receptor-mediated cell signaling. RGS2 is an RGS protein that shows preference toward Gαq. To better understand the role of RGS2 in Ca2+ signaling and Ca2+ oscillations, we characterized Ca2+ signaling in cells derived from RGS2 -/- mice. Deletion of RGS2 modified the kinetic of inositol 1,4,5-trisphosphate (IP3) production without affecting the peak level of IP3, but rather increased the steady-state level of IP 3 at all agonist concentrations. The increased steady-state level of IP3 led to an increased frequency of [Ca2+]i oscillations. The cells were adapted to deletion of RGS2 by reducing Ca 2+ signaling excitability. Reduced excitability was achieved by adaptation of all transporters to reduce Ca2+ influx into the cytosol. Thus, IP3 receptor 1 was down-regulated and IP3 receptor 3 was up-regulated in RGS2-/- cells to reduce the sensitivity for IP3 to release Ca2+ from the endoplasmic reticulum to the cytosol. Sarco/endoplasmic reticulum Ca2+ ATPase 2b was upregulated to more rapidly remove Ca2+ from the cytosol of RGS2-/- cells. Agonist-stimulated Ca2+ influx was reduced, and Ca2+ efflux by plasma membrane Ca2+ was up-regulated in RGS2-/- cells. The result of these adaptive mechanisms was the reduced excitability of Ca2+ signaling, as reflected by the markedly reduced response of RGS2-/- cells to changes in the endoplasmic reticulum Ca2+ load and to an increase in extracellular Ca 2+. These findings highlight the central role of RGS proteins in [Ca2+]i oscillations and reveal a prominent plasticity and adaptability of the Ca2+ signaling apparatus.

Original languageEnglish (US)
Pages (from-to)41642-41649
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number40
DOIs
StatePublished - Oct 1 2004

Fingerprint

GTP-Binding Protein Regulators
RGS Proteins
Cytosol
Inositol 1,4,5-Trisphosphate Receptors
Endoplasmic Reticulum
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Cell signaling
Inositol 1,4,5-Trisphosphate
GTP Phosphohydrolases
Cell membranes
G-Protein-Coupled Receptors
Plasticity
Cell Membrane

ASJC Scopus subject areas

  • Biochemistry

Cite this

Role of regulator of G protein signaling 2 (RGS2) in Ca2+ oscillations and adaptation of Ca2+ signaling to reduce excitability of RGS2-/- cells. / Wang, Xinhua; Huang, Guojin; Luo, Xiang; Penninger, Josef M.; Muallem, Shmuel.

In: Journal of Biological Chemistry, Vol. 279, No. 40, 01.10.2004, p. 41642-41649.

Research output: Contribution to journalArticle

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abstract = "Regulators of G protein signaling (RGS) proteins accelerate the GTPase activity of Gα subunits to determine the duration of the stimulated state and control G protein-coupled receptor-mediated cell signaling. RGS2 is an RGS protein that shows preference toward Gαq. To better understand the role of RGS2 in Ca2+ signaling and Ca2+ oscillations, we characterized Ca2+ signaling in cells derived from RGS2 -/- mice. Deletion of RGS2 modified the kinetic of inositol 1,4,5-trisphosphate (IP3) production without affecting the peak level of IP3, but rather increased the steady-state level of IP 3 at all agonist concentrations. The increased steady-state level of IP3 led to an increased frequency of [Ca2+]i oscillations. The cells were adapted to deletion of RGS2 by reducing Ca 2+ signaling excitability. Reduced excitability was achieved by adaptation of all transporters to reduce Ca2+ influx into the cytosol. Thus, IP3 receptor 1 was down-regulated and IP3 receptor 3 was up-regulated in RGS2-/- cells to reduce the sensitivity for IP3 to release Ca2+ from the endoplasmic reticulum to the cytosol. Sarco/endoplasmic reticulum Ca2+ ATPase 2b was upregulated to more rapidly remove Ca2+ from the cytosol of RGS2-/- cells. Agonist-stimulated Ca2+ influx was reduced, and Ca2+ efflux by plasma membrane Ca2+ was up-regulated in RGS2-/- cells. The result of these adaptive mechanisms was the reduced excitability of Ca2+ signaling, as reflected by the markedly reduced response of RGS2-/- cells to changes in the endoplasmic reticulum Ca2+ load and to an increase in extracellular Ca 2+. These findings highlight the central role of RGS proteins in [Ca2+]i oscillations and reveal a prominent plasticity and adaptability of the Ca2+ signaling apparatus.",
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