Synergistic activation of phospholipase C-β3 by Gαq and Gβγ describes a simple two-state coincidence detector

Finly Philip, Ganesh Kadamur, Rosa González Silos, Jimmy Woodson, Elliott M. Ross

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Background: Receptors that couple to Gi and Gq often interact synergistically in cells to elicit cytosolic Ca2+ transients that are several-fold higher than the sum of those driven by each receptor alone. Such synergism is commonly assumed to be complex, requiring regulatory interaction between components, multiple pathways, or multiple states of the target protein. Results: We show that cellular Gi-Gq synergism derives from direct supra-additive stimulation of phospholipase C-β3 (PLC-β3) by G protein subunits Gβγ and Gαq, the relevant components of the Gi and G q signaling pathways. No additional pathway or proteins are required. Synergism is quantitatively explained by the classical and simple two-state (inactive↔active) allosteric mechanism. We show generally that synergistic activation of a two-state enzyme reflects enhanced conversion to the active state when both ligands are bound, not merely the enhancement of ligand affinity predicted by positive cooperativity. The two-state mechanism also explains why synergism is unique to PLC-β3 among the four PLC-β isoforms and, in general, why one enzyme may respond synergistically to two activators while another does not. Expression of synergism demands that an enzyme display low basal activity in the absence of ligand and becomes significant only when basal activity is ≤ 0.1% of maximal. Conclusions: Synergism can be explained by a simple and general mechanism, and such a mechanism sets parameters for its occurrence. Any two-state enzyme is predicted to respond synergistically to multiple activating ligands if, but only if, its basal activity is strongly suppressed.

Original languageEnglish (US)
Pages (from-to)1327-1335
Number of pages9
JournalCurrent Biology
Volume20
Issue number15
DOIs
StatePublished - Aug 10 2010

Keywords

  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Fingerprint Dive into the research topics of 'Synergistic activation of phospholipase C-β3 by Gα<sub>q</sub> and Gβγ describes a simple two-state coincidence detector'. Together they form a unique fingerprint.

Cite this