Gqprotein Alpha subunitis a family ofheterotrimeric G proteinAlpha subunits.This family is also commonly called theGq/11(Gq/G11) family orGq/11/14/15family to include closely related family members. G Alpha subunits may be referred to as GqAlpha, Gαq,or Gqα. Gqproteins couple toG protein-coupled receptorsto activate beta-typephospholipase C(PLC-β) enzymes. PLC-β in turn hydrolyzesphosphatidylinositol 4,5-bisphosphate(PIP2) todiacyl glycerol(DAG) andinositol trisphosphate(IP3). IP3acts as asecond messengerto release stored calcium into the cytoplasm, while DAG acts as a second messenger that activatesprotein 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. 9q21 | ||||||
| |||||||
| 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. 19p13.3 | ||||||
| |||||||
| 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. 9q21 | ||||||
| |||||||
| 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. 19p13.3 | ||||||
| |||||||
Family members
editIn humans, there are four distinct proteins in the GqAlpha subunit family:
Function
editThe general function of Gqis to activateintracellular signaling pathwaysin response to activation of cell surfaceG 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 aheterotrimeric 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 aGβγ complex.[1][2]When not stimulated by a receptor, Gα is bound toguanosine 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 ahormoneorneurotransmitter), the activated receptor acts as aguanine nucleotide exchange factorto promote GDP release from andguanosine 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.
Gq/11/14/15proteins all activate beta-typephospholipase C(PLC-β) to signal through calcium and PKC signaling pathways.[4]PLC-β then cleaves a specificplasma membranephospholipid,phosphatidylinositol 4,5-bisphosphate(PIP2) intodiacyl glycerol(DAG) andinositol 1,4,5-trisphosphate(IP3). DAG remains bound to the membrane, and IP3is released as a soluble molecule into thecytoplasm.IP3diffuses to bind toIP3receptors,a specializedcalcium channelin theendoplasmic reticulum(ER). These channels are specific tocalciumand 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
editThe followingG protein-coupled receptorscouple to Gqsubunits:
- 5-HT2serotonergic receptors
- Alpha-1 adrenergic receptor
- Vasopressin type 1 receptors:1Aand1B
- Angiotensin II receptor type 1
- Calcitonin receptor
- GlutamatemGluR1andmGluR5receptors
- Gonadotropin-releasing hormone receptor
- Histamine H1 receptor
- M1,M3,andM5muscarinic receptors[7]
- Thyrotropin-releasing hormone receptor
- Trace amine-associated receptor 1
At least some Gq-coupled receptors (e.g., the muscarinic acetylcholine M3receptor) 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.[7]
Inhibitors
editSee also
editReferences
edit- ^abcdGilman AG (1987). "G proteins: transducers of receptor-generated signals".Annual Review of Biochemistry.56:615–649.doi:10.1146/annurev.bi.56.070187.003151.PMID3113327.
- ^abcdRodbell M (1995)."Nobel Lecture: Signal transduction: Evolution of an idea".Bioscience Reports.15(3): 117–133.doi:10.1007/bf01207453.PMC1519115.PMID7579038.S2CID11025853.
- ^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.PMC6333895.PMID30446620.
- ^abcAlberts B, Lewis J, Raff M, Roberts K, Walter P (2002).Molecular biology of the cell(4th ed.). New York: Garland Science.ISBN0-8153-3218-1.
- ^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.PMC6279241.PMID30181242.
- ^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.PMID30890659.S2CID84183146.
- ^abQin 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.PMC3177959.PMID21873996.
- ^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.PMC8033771.PMID33860209.
- ^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.PMID33998635.S2CID234748014.
External links
edit- Gq+proteinat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
