Gq alpha subunit

{{Short description|Family of heterotrimeric G protein alpha subunits}} {{DISPLAYTITLE:G_q alpha subunit}} {{infobox protein | Name = guanine nucleotide binding protein (G protein), q polypeptide | caption = | image = | width = | HGNCid = 4390 | Symbol = GNAQ | AltSymbols = | EntrezGene = 2776 | OMIM = 600998 | RefSeq = NM_002072 | UniProt = P50148 | PDB = | ECnumber = | Chromosome = 9 | Arm = q | Band = 21 | LocusSupplementaryData = }} {{infobox protein | Name = guanine nucleotide binding protein (G protein), alpha 11 (Gq class) | caption = | image = | width = | HGNCid = 4379 | Symbol = GNA11 | AltSymbols = | EntrezGene = 2767 | OMIM = 139313 | RefSeq = NM_002067 | UniProt = P29992 | PDB = | ECnumber = | Chromosome = 19 | Arm = p | Band = 13.3 | LocusSupplementaryData = }} {{infobox protein | Name = guanine nucleotide binding protein (G protein), alpha 14 | caption = | image = | width = | HGNCid = 4382 | Symbol = GNA14 | AltSymbols = | EntrezGene = 9630 | OMIM = 604397 | RefSeq = NM_004297 | UniProt = O95837 | PDB = | ECnumber = | Chromosome = 9 | Arm = q | Band = 21 | LocusSupplementaryData = }} {{infobox protein | Name = guanine nucleotide binding protein (G protein), alpha 15 (Gq class) | caption = | image = | width = | HGNCid = 4383 | Symbol = GNA15 | AltSymbols = | EntrezGene = 2769 | OMIM = 139314 | RefSeq = NM_002068 | UniProt = P30679 | PDB = | ECnumber = | Chromosome = 19 | Arm = p | Band = 13.3 | LocusSupplementaryData = }}

'''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).

== 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|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.<ref name="pmid3113327">{{cite journal | vauthors = Gilman AG |date=1987 |title= G proteins: transducers of receptor-generated signals |journal= Annual Review of Biochemistry |volume=56 |pages=615–649 |doi=10.1146/annurev.bi.56.070187.003151 |pmid=3113327 }}</ref><ref name="pmid7579038">{{cite journal | vauthors = Rodbell M |date=1995 |title=Nobel Lecture: Signal transduction: Evolution of an idea |journal=Bioscience Reports |volume=15 |issue=3 |pages=117–133 |doi=10.1007/bf01207453 |pmid=7579038 |pmc=1519115 |s2cid=11025853 }}</ref> 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.<ref name="pmid3113327"/><ref name="pmid7579038"/> When not stimulated by a receptor, Gα is bound to guanosine diphosphate (GDP) and to Gβγ to form the inactive G protein trimer.<ref name="pmid3113327"/><ref name="pmid7579038"/> 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.<ref name="pmid3113327"/><ref name="pmid7579038"/> Recent evidence suggests that Gβγ and Gαq-GTP could maintain partial interaction via the N-α-helix region of Gαq.<ref>{{cite journal | vauthors = 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 | title = Gβγ Signaling to the Chemotactic Effector P-REX1 and Mammalian Cell Migration Is Directly Regulated by Gαqand Gα13 Proteins | journal=J Biol Chem | volume = 294 | issue = 2 | pages = 531–546 | date = January 2019 | pmid = 30446620 | pmc = 6333895 | doi = 10.1074/jbc.RA118.006254 | doi-access = free }}</ref> 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.<ref name="alberts">{{cite book |vauthors=Alberts B, Lewis J, Raff M, Roberts K, Walter P | title = Molecular biology of the cell |url=https://archive.org/details/molecularbiolog000wils |url-access=registration | publisher = Garland Science | location = New York | edition = 4th | year = 2002 | isbn = 0-8153-3218-1 }}</ref> 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.<ref name=alberts/>

: ''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.<ref name="alberts"/>

: ''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.<ref>{{cite journal | vauthors = Onken MD, Makepeace CM, Kaltenbronn KM, Kanai SM, Todd TD, Wang S, Broekelmann TJ, Rao PK, Cooper JA, Blumer KJ| title = Targeting nucleotide exchange to inhibit constitutively active G protein alpha subunits in cancer cells | journal=Sci Signal | volume = 11 | issue = 546 | pages = 6852 | date = September 2018 | article-number = eaao6852 | pmid = 30181242 | doi = 10.1126/scisignal.aao6852 | pmc = 6279241 | doi-access = free }}</ref><ref>{{cite journal | vauthors = 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| title = Direct Targeting of Gαq and Gα11 Oncoproteins in Cancer Cells | journal=Sci Signal | volume = 12 | issue = 573 | pages = 5948 | date = March 2019 | article-number = eaau5948 | pmid = 30890659 | doi = 10.1126/scisignal.aau5948 | s2cid = 84183146 | doi-access = free }}</ref>

== 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<ref name="Kou Qin"/> * 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.<ref name="Kou Qin">{{Cite journal|vauthors=Qin K, Dong C, Wu G, Lambert NA |date=August 2011 | title = Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers| journal = Nature Chemical Biology| volume = 7 | issue = 11| pages =740–747|doi=10.1038/nchembio.642 | pmid=21873996|pmc=3177959}}</ref>

== Inhibitors == * The cyclic depsipeptides FR900359 and YM-254890 are strong, highly specific inhibitors of Gq and G11.<ref name="pmid33860209">{{cite journal | vauthors = Schlegel JG, Tahoun M, Seidinger A, Voss JH, Kuschak M, Kehraus S, Schneider M, Matthey M, Fleischmann BK, König GM, Wenzel D, Müller CE |date= 2021 |title= Macrocyclic Gq Protein Inhibitors FR900359 and/or YM-254890 - Fit for Translation? |journal= ACS Pharmacology & Translational Science |volume= 4 |issue= 2 |pages= 888–897 |doi=10.1021/acsptsci.1c00021 |pmid=33860209 |pmc=8033771 }}</ref><ref name="pmid33998635">{{cite journal | vauthors = Hermes C, König GM, Crüsemann M |date= 2021 |title= The chromodepsins - chemistry, biology and biosynthesis of a selective Gq inhibitor natural product family |journal= Natural Product Reports|volume= 38 |issue= 12 |pages= 2276–2292 |doi=10.1039/d1np00005e |pmid=33998635 |s2cid= 234748014 |url= https://pubs.rsc.org/en/content/articlelanding/2021/NP/D1NP00005E |url-access= subscription }}</ref>

== 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 == {{Reflist}}

== External links == * {{MeshName|Gq+protein}}

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Category:G proteins Category:Peripheral membrane proteins