Several studies have reported that activation of Gq-coupled receptors inhibits PI3K (phosphoinositide 3-kinase) signalling. In the present study, we used purified proteins to demonstrate that Gαq directly inhibits p110α/p85α PI3K in a GTP-dependent manner. Activated Gαq binds to the p110α/p85α PI3K with an apparent affinity that is seven times stronger than that for Gαq·GDP as measured by fluorescence spectroscopy. In contrast, Gαq did not bind to the p110γ PI3K. Fluorescence spectroscopy experiments also showed that Gαq competes with Ras, a PI3K activator, for binding to p110α/p85α. Interestingly, co-precipitation studies using deletion mutants showed that Gαq binds to the p85-binding domain of p110α and not to the Ras-binding domain. Expression of constitutively active GαqQ209L in cells inhibited Ras activation of the PI3K/Akt pathway but had no effect on Ras/Raf/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] signalling. These results suggest that activation of Gq-coupled receptors leads to increased binding of Gαq·GTP to some isoforms of PI3K, which might explain why these receptors inhibit this signalling pathway in certain cell types.

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