title: Decoding Gαq signaling.
abstract: Gαq signals with phospholipase C-β (PLC-β) to modify behavior in response to an agonist-bound GPCR. While the fundamental steps which prime Gαq to interact with PLC-β have been identified, questions remain concerning signal strength with PLC-β and other effectors. Gαq is generally viewed to function as a simple ON and OFF switch for its effector, dependent on the binding of GTP or GDP. However, Gαq does not have a single effector, Gαq has many different effectors. Furthermore, select effectors also regulate Gαq activity. PLC-β is a lipase and a GTPase activating protein (GAP) selective for Gαq. The contribution of G protein regulating activity to signal amplitude remains unclear. The unique PLC-β coiled-coil domain is essential for maximum Gαq response, both lipase and GAP. Nonetheless, coiled-coil domain associations necessary to maximum response have not been revealed by the structural approach. This review discusses progress towards understanding the basis for signal strength with PLC-β and other effectors. Shared and effector-specific interactions have been identified. Finally, the evidence for allosteric regulation of lipase stimulation by protein kinase C, the membrane, phosphatidic acid, phosphatidylinositol-4, 5-bisphosphate and GPCR is explored. Endogenous allosteric regulators can suppress or enhance maximum lipase stimulation dependent on the PLC-β coiled-coil domain. A better understanding of allosteric modulation may therefore identify a wealth of new targets to regulate signal strength and behavior.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine University of Miami, Miami, FL 33101-6189, USA. Electronic address: ilitosch@med.miami.edu.
authors.forename: Irene
authors.initials: I
authors.lastname: Litosch
mesh_terms: D000818:Animals; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D054799:Phospholipase C beta / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D043562:Receptors, G-Protein-Coupled; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: Diacylglycerol kinase; Effectors; G protein regulated kinase 2; G protein-coupled receptor; GTPase activating protein; Gα(q); Phosphatidic acid; Phosphatidylinositol-3 kinase; Phosphatidylinositol-4,5 bisphosphate; Phospholipase C-β; Phospholipase C-ε; Protein kinase C; Tetratricopeptide repeat 1; Transient receptor potential cation channel 8; p63RhoGEF