Current Biology
Volume 20, Issue 15, 10 August 2010, Pages 1327-1335
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Article
Synergistic Activation of Phospholipase C-β3 by Gαq and Gβγ Describes a Simple Two-State Coincidence Detector

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Summary

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 Gq 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.

Highlights

► Phospholipase C-β3 (PLC-β3) responds to Gαq and Gβγ 10-fold more than additively ► Gαq-Gβγ synergism explains synergistic cellular Ca2+ responses to Gi and Gq pathways ► A two-state mechanism explains why PLC-β3 displays synergism and other PLC-βs don't ► Coincidence detection requires only that targets enzyme have very low basal activity

SIGNALING

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