G<sub>q</sub> protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the G<sub>q/11</sub> (G<sub>q</sub>/G<sub>11</sub>) family or G<sub>q/11/14/15</sub> family to include closely related family members. G alpha subunits may be referred to as G<sub>q</sub> alpha, G<sub>ñq</sub>, or G<sub>q</sub>ñ. G<sub>q</sub> proteins couple to G protein-coupled receptors to activate beta-type phospholipase C (PLC-ò) enzymes. PLC-ò in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>) to diacyl glycerol (DAG) and inositol trisphosphate (IP<sub>3</sub>). IP<sub>3</sub> acts as a second messenger to release stored calcium into the cytoplasm, while DAG acts as a second messenger that activates protein kinase C (PKC).
In humans, there are four distinct proteins in the G<sub>q</sub> alpha subunit family:
The general function of G<sub>q</sub> is to activate intracellular signaling pathways in response to activation of cell surface G protein-coupled receptors (GPCRs). GPCRs function as part of a three-component system of receptor-transducer-effector. The transducer in this system is a heterotrimeric G protein, composed of three subunits: a Gñ protein such as G<sub>ñq</sub>, and a complex of two tightly linked proteins called Gò and Gó in a Gòó complex. When not stimulated by a receptor, Gñ is bound to guanosine diphosphate (GDP) and to Gòó to form the inactive G protein trimer. When the receptor binds an activating ligand outside the cell (such as a hormone or neurotransmitter), the activated receptor acts as a guanine nucleotide exchange factor to promote GDP release from and guanosine triphosphate (GTP) binding to Gñ, which drives dissociation of GTP-bound Gñ from Gòó. Recent evidence suggests that Gòó and Gñq-GTP could maintain partial interaction via the N-ñ-helix region of Gñq. GTP-bound Gñ and Gòó are then freed to activate their respective downstream signaling enzymes.
G<sub>q/11/14/15</sub> proteins all activate beta-type phospholipase C (PLC-ò) to signal through calcium and PKC signaling pathways. PLC-ò then cleaves a specific plasma membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP<sub>3</sub>). DAG remains bound to the membrane, and IP<sub>3</sub> is released as a soluble molecule into the cytoplasm. IP<sub>3</sub> diffuses to bind to IP<sub>3</sub> receptors, a specialized calcium channel in the endoplasmic reticulum (ER). These channels are specific to calcium and only allow the passage of calcium from the ER into the cytoplasm. Since cells actively sequester calcium in the ER to keep cytoplasmic levels low, this release causes the cytosolic concentration of calcium to increase, causing a cascade of intracellular changes and activity through calcium binding proteins and calcium-sensitive processes.
DAG works together with released calcium to activate specific isoforms of PKC, which are activated to phosphorylate other molecules, leading to further altered cellular activity.
The Gñq / Gñ11 (Q209L) mutation is associated with the development of uveal melanoma and its pharmacological inhibition (cyclic depsipeptide FR900359 inhibitor), decreases tumor growth in preclinical trials.
The following G protein-coupled receptors couple to G<sub>q</sub> subunits:
At least some Gq-coupled receptors (e.g., the muscarinic acetylcholine M<sub>3</sub> receptor) can be found preassembled (pre-coupled) with G<sub>q</sub>. The common polybasic domain in the C-tail of G<sub>q</sub>-coupled receptors appears necessary for this receptorìG protein preassembly.