TY - JOUR
T1 - Synergistic activation of phospholipase C-β3 by Gαq and Gβγ describes a simple two-state coincidence detector
AU - Philip, Finly
AU - Kadamur, Ganesh
AU - Silos, Rosa González
AU - Woodson, Jimmy
AU - Ross, Elliott M.
N1 - Funding Information:
We thank multiple colleagues at University of Texas Southwestern for valuable discussion; William Seaman, Robert Rebres, and Tamara Roach (University of California San Francisco) for sharing unpublished results; Paul Sternweis (UT Southwestern) for the PLC-β2 baculovirus and PLC-β3 cDNA; and Iain Frasier (National Institute of Allergy and Infectious Diseases) for the PLC-β4 cDNA. This work was supported by National Institutes of Health (NIH) grant R01GM030355 and an American Recovery and Reinvestment Act competing supplement, and by Welch Foundation grant I-0982.
PY - 2010/8/10
Y1 - 2010/8/10
N2 - 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.
AB - 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.
KW - SIGNALING
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U2 - 10.1016/j.cub.2010.06.013
DO - 10.1016/j.cub.2010.06.013
M3 - Article
C2 - 20579885
AN - SCOPUS:77955508883
SN - 0960-9822
VL - 20
SP - 1327
EP - 1335
JO - Current Biology
JF - Current Biology
IS - 15
ER -