G protein co-signaling and challenges for translational research

Irene Litosch

Research output: Contribution to journalReview article

3 Scopus citations

Abstract

The Gq-linked G protein coupled receptors (GPCRs) and their signaling pathways are important clinical targets for the dementia of Alzheimer's disease and cognitive decline with aging. Gq stimulates phospholipase C-β1 (PLC-β1) activity, increasing levels of inositol-1, 4, 5-trisphosphate (IP3) and diacylglycerol, to initiate mobilization of intracellular Ca2+ and activation of protein kinase C, respectively. While high concentrations of ligand typically evoke large sustained increases in cytosolic Ca2+ levels, it has long been appreciated that the dynamics of the Ca2+ increase are more complex and consistent with multiple levels of regulation. Physiologically relevant concentrations of Gq-ligands evoke rhythmic fluctuations or an oscillation in the level of cytosolic Ca2+. Downstream targets are tuned to respond to the frequency of the Ca2+ oscillations which in turn, reflect the oscillations in IP3 levels. Oscillatory behavior depends on the assembly of self-organizing interactions. The components that contribute to and regulate the Ca2+ oscillator have been unclear, precluding transfer of this fundamental knowledge from bench to bedside. Many GPCRs that signal with Gq also co-signal with G12. G protein co-signaling could therefore regulate the Ca2+ oscillator. This letter explores the potential relationship between Ca2+ oscillations, G protein co-signaling and cellular response in the context of our recent observations. We found that Gq efficacy is synergistic with phosphatidic acid, (PA), a signaling mediator generated downstream of activated G12 and RhoA. Regulation by PA depends on interaction with the unique PLC-β1 PA binding region. G protein co-signaling is therefore a mechanism for GPCRs to collectively assemble self-organizing interactions that regulate the Ca2+ oscillator.

Original languageEnglish (US)
Pages (from-to)66-73
Number of pages8
JournalTranslational Neuroscience
Volume4
Issue number1
DOIs
StatePublished - Mar 1 2013

Keywords

  • Ca oscillations
  • Diacylglycerol kinase
  • G
  • G protein co-signaling
  • G
  • GPCR
  • Phosphatidic acid
  • Phospholipase C-β
  • Phospholipase D
  • Protein kinase C

ASJC Scopus subject areas

  • Neuroscience(all)

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