Novel Mechanisms for Feedback Regulation of Phospholipase C‐β Activity

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Abstract
The receptor‐regulated phospholipase C‐ β(PLC‐ β) signaling pathway is an important component in a network of signaling cascades that regulate cell function. PLC‐ βsignaling has been implicated in the regulation of cardiovascular function and neuronal plasticity. The G q family of G proteins mediate receptor stimulation of PLC‐ βactivity at the plasma membrane. Mitogens stimulate the activity of a nuclear pool of PLC‐ β. Stimulation of PLC‐ βactivity results in the rapid hydrolysis of phosphatidylinositol‐4,5‐bisphosphate, with production of inositol‐1,4,5‐trisphosphate and diacylglycerol, intracellular mediators that increase intracellular Ca 2+ levels and activate protein kinase C activity, respectively. Diacylglycerol kinase converts diacylglycerol to phosphatidic acid, a newly emerging intracellular mediator of hormone action that targets a number of signaling proteins. Activation of the G q linked PLC‐ βsignaling pathway can also generate additional signaling lipids, including phosphatidylinositol‐3‐phosphate and phosphatidylinositol‐3,4,5‐trisphosphate, which regulate the activity and/or localization of a number of proteins. Novel feedback mechanisms, directed at the level of G q and PLC‐ β, have been identified. PLC‐ βand regulators of G protein signaling (RGS) function as GTPase‐activating proteins on G q to control the amplitude and duration of stimulation. Protein kinases phosphorylate and regulate the activation of specific PLC‐ βisoforms. Phosphatidic acid regulates PLC‐ β1 activity and stimulation of PLC‐ β1 activity by G proteins. These feedback mechanisms coordinate receptor signaling and cell activation. Feedback mechanisms constitute possible targets for pharmacological intervention in the treatment of disease.

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