Gq alpha subunit

G_q protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the G_q/11 (G_q/G₁₁) family or G_q/11/14/15 family to include closely related family members. G alpha subunits may be referred to as G_q alpha, G_αq, or G_qα. G_q proteins couple to G protein-coupled receptors to activate beta-type phospholipase C (PLC-β) enzymes. PLC-β in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) to diacyl glycerol (DAG) and inositol trisphosphate (IP₃). IP₃ 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).

guanine nucleotide binding protein (G protein), q polypeptide
Identifiers
Symbol	GNAQ
NCBI gene	2776
HGNC	4390
OMIM	600998
RefSeq	NM_002072
UniProt	P50148
Other data
Locus	Chr. 9 q21
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guanine nucleotide binding protein (G protein), alpha 11 (Gq class)
Identifiers
Symbol	GNA11
NCBI gene	2767
HGNC	4379
OMIM	139313
RefSeq	NM_002067
UniProt	P29992
Other data
Locus	Chr. 19 p13.3
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guanine nucleotide binding protein (G protein), alpha 14
Identifiers
Symbol	GNA14
NCBI gene	9630
HGNC	4382
OMIM	604397
RefSeq	NM_004297
UniProt	O95837
Other data
Locus	Chr. 9 q21
Search for Structures Swiss-model Domains InterPro

guanine nucleotide binding protein (G protein), alpha 15 (Gq class)
Identifiers
Symbol	GNA15
NCBI gene	2769
HGNC	4383
OMIM	139314
RefSeq	NM_002068
UniProt	P30679
Other data
Locus	Chr. 19 p13.3
Search for Structures Swiss-model Domains InterPro

Family members

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

• G_αq is encoded by the gene GNAQ.
• G_α11 is encoded by the gene GNA11.
• G_α14 is encoded by the gene GNA14.
• G_α15 is encoded by the gene GNA15.

Function

Main article: Heterotrimeric G protein

The general function of G_q 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.^[1][2] The transducer in this system is a heterotrimeric G protein, composed of three subunits: a Gα protein such as G_αq, and a complex of two tightly linked proteins called Gβ and Gγ in a Gβγ complex.^[1][2] When not stimulated by a receptor, Gα is bound to guanosine diphosphate (GDP) and to Gβγ to form the inactive G protein trimer.^[1][2] 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.^[1][2] Recent evidence suggests that Gβγ and Gαq-GTP could maintain partial interaction via the N-α-helix region of Gαq.^[3] GTP-bound Gα and Gβγ are then freed to activate their respective downstream signaling enzymes.

G_q/11/14/15 proteins all activate beta-type phospholipase C (PLC-β) to signal through calcium and PKC signaling pathways.^[4] 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.^[4]

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.^[4]

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.^[5][6]

Receptors

The following G protein-coupled receptors couple to G_q 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^[7]
• 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 G_q. The common polybasic domain in the C-tail of G_q-coupled receptors appears necessary for this receptor¬G protein preassembly.^[7]

Inhibitors

• The cyclic depsipeptides FR900359 and YM-254890 are strong, highly specific inhibitors of Gq and G11.^[8][9]

See also

• Second messenger system
• G protein-coupled receptor
• Heterotrimeric G protein
• Phospholipase C
• Calcium signaling
• Protein kinase C
• Gs alpha subunit
• Gi alpha subunit
• G12/G13 alpha subunits

References

1. Gilman AG (1987). "G proteins: transducers of receptor-generated signals". Annual Review of Biochemistry. 56: 615–649. doi:10.1146/annurev.bi.56.070187.003151. PMID 3113327.
2. Rodbell M (1995). "Nobel Lecture: Signal transduction: Evolution of an idea". Bioscience Reports. 15 (3): 117–133. doi:10.1007/bf01207453. PMC 1519115. PMID 7579038. S2CID 11025853.
3. Cervantes-Villagrana RD, Adame-García SR, García-Jiménez I, Color-Aparicio VM, Beltrán-Navarro YM, König GM, Kostenis E, Reyes-Cruz G, Gutkind JS, Vázquez-Prado J (January 2019). "Gβγ Signaling to the Chemotactic Effector P-REX1 and Mammalian Cell Migration Is Directly Regulated by Gαqand Gα13 Proteins". J Biol Chem. 294 (2): 531–546. doi:10.1074/jbc.RA118.006254. PMC 6333895. PMID 30446620.
4. Alberts B, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1.
5. Onken MD, Makepeace CM, Kaltenbronn KM, Kanai SM, Todd TD, Wang S, Broekelmann TJ, Rao PK, Cooper JA, Blumer KJ (September 2018). "Targeting nucleotide exchange to inhibit constitutively active G protein alpha subunits in cancer cells". Sci Signal. 11 (546): 6852. doi:10.1126/scisignal.aao6852. PMC 6279241. PMID 30181242.
6. Annala S, Feng X, Shridhar N, Eryilmaz F, Patt J, Yang J, Pfeil EM, Cervantes-Villagrana RD, Inoue A, Häberlein F, Slodczyk T, Reher R, Kehraus S, Monteleone S, Schrage R, Heycke N, Rick U, Engel S, Pfeifer A, Kolb P, König GM, Kostenis E, Bünemann M, Tüting T, Vázquez-Prado J, Gutkind JS, Gaffal E, Kostenis E (March 2019). "Direct Targeting of Gαq and Gα11 Oncoproteins in Cancer Cells". Sci Signal. 12 (573): 5948. doi:10.1126/scisignal.aau5948. PMID 30890659. S2CID 84183146.
7. Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers". Nature Chemical Biology. 7 (11): 740–747. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
8. Schlegel JG, Tahoun M, Seidinger A, Voss JH, Kuschak M, Kehraus S, Schneider M, Matthey M, Fleischmann BK, König GM, Wenzel D, Müller CE (2021). "Macrocyclic Gq Protein Inhibitors FR900359 and/or YM-254890 - Fit for Translation?". ACS Pharmacology & Translational Science. 4 (2): 888–897. doi:10.1021/acsptsci.1c00021. PMC 8033771. PMID 33860209.
9. Hermes C, König GM, Crüsemann M (2021). "The chromodepsins - chemistry, biology and biosynthesis of a selective Gq inhibitor natural product family". Natural Product Reports. 38 (12): 2276–2292. doi:10.1039/d1np00005e. PMID 33998635. S2CID 234748014.

External links

• Gq+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)