Gq alpha subunit

Family members

In humans, there are four distinct proteins in the Gq alpha subunit family:

• Gαq is encoded by the gene GNAQ.
• Gα11 is encoded by the gene GNA11.
• Gα14 is encoded by the gene GNA14.
• Gα15 is encoded by the gene GNA15.

Function

Main article: Heterotrimeric G protein

The general function of Gq 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 Gα protein such as Gαq, and a complex of two tightly linked proteins called Gβ and Gγ in a Gβγ complex. When not stimulated by a receptor, Gα is bound to guanosine diphosphate (GDP) and to Gβγ 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 Gα, which drives dissociation of GTP-bound Gα from Gβγ. Recent evidence suggests that Gβγ and Gαq-GTP could maintain partial interaction via the N-α-helix region of Gαq. GTP-bound Gα and Gβγ are then freed to activate their respective downstream signaling enzymes.

Gq/11/14/15 proteins all activate beta-type phospholipase C (PLC-β) to signal through calcium and PKC signaling pathways. PLC-β then cleaves a specific plasma membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG remains bound to the membrane, and IP3 is released as a soluble molecule into the cytoplasm. IP3 diffuses to bind to IP3 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.

: Further reading: Calcium function in vertebrates

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.

: Further reading: function of protein kinase C

The Gαq / Gα11 (Q209L) mutation is associated with the development of uveal melanoma and its pharmacological inhibition (cyclic depsipeptide FR900359 inhibitor), decreases tumor growth in preclinical trials.

Receptors

The following G protein-coupled receptors couple to Gq subunits:

• 5-HT2 serotonergic receptors
• Alpha-1 adrenergic receptor
• Vasopressin type 1 receptors: 1A and 1B
• Angiotensin II receptor type 1
• Calcitonin receptor
• Glutamate mGluR1 and mGluR5 receptors
• Gonadotropin-releasing hormone receptor
• Histamine H1 receptor
• M1, M3, and M5 muscarinic receptors
• Thyrotropin-releasing hormone receptor
• Trace amine-associated receptor 1

At least some Gq-coupled receptors (e.g., the muscarinic acetylcholine M3 receptor) can be found preassembled (pre-coupled) with Gq. The common polybasic domain in the C-tail of Gq-coupled receptors appears necessary for this receptor¬G protein preassembly.

Inhibitors

• The cyclic depsipeptides FR900359 and YM-254890 are strong, highly specific inhibitors of Gq and G11.

References

References

1. (1987). "G proteins: transducers of receptor-generated signals". Annual Review of Biochemistry.
2. (1995). "Nobel Lecture: Signal transduction: Evolution of an idea". Bioscience Reports.
3. (January 2019). "Gβγ Signaling to the Chemotactic Effector P-REX1 and Mammalian Cell Migration Is Directly Regulated by Gαqand Gα13 Proteins". J Biol Chem.
4. (2002). "Molecular biology of the cell". Garland Science.
5. (September 2018). "Targeting nucleotide exchange to inhibit constitutively active G protein alpha subunits in cancer cells". Sci Signal.
6. (March 2019). "Direct Targeting of Gαq and Gα11 Oncoproteins in Cancer Cells". Sci Signal.
7. (August 2011). "Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers". Nature Chemical Biology.
8. (2021). "Macrocyclic Gq Protein Inhibitors FR900359 and/or YM-254890 - Fit for Translation?". ACS Pharmacology & Translational Science.
9. (2021). "The chromodepsins - chemistry, biology and biosynthesis of a selective Gq inhibitor natural product family". Natural Product Reports.