Editing G protein (section)

== Signaling ==
G protein can refer to two distinct families of proteins. [[Heterotrimeric G protein]]s, sometimes referred to as the "large" G proteins, are activated by [[G protein-coupled receptor]]s and are made up of alpha (α), beta (β), and gamma (γ) [[Protein subunit|subunit]]s. ''"Small" G proteins'' (20-25kDa) belong to the [[Ras (protein)|Ras]] superfamily of [[small GTPase]]s. These proteins are [[Sequence homology|homologous]] to the alpha (α) subunit found in heterotrimers, but are in fact monomeric, consisting of only a single unit. However, like their larger relatives, they also bind GTP and GDP and are involved in [[signal transduction]].

=== Heterotrimeric ===
{{Main|Heterotrimeric G proteins}}
Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to a [[conformational change]] in the GPCR, exchanging GDP for GTP, and dissociating in order to activate other proteins in a particular [[signal transduction]] pathway.<ref>{{Cite book|last=Lim|first=Wendell|url=https://www.worldcat.org/oclc/868641565|title=Cell signaling : principles and mechanisms|date=2015|others=Bruce Mayer, T. Pawson|isbn=978-0-8153-4244-1|location=New York|oclc=868641565}}</ref> The specific mechanisms, however, differ between protein types.

===Mechanism===
[[File:GPCR-Zyklus.png|thumb|450px|Activation cycle of G-proteins (pink) by a G-protein-coupled receptor (GPCR, light blue) receiving a ligand (red). Ligand binding to GPCRs (2) induces a conformation change that facilitates the exchange of GDP for GTP on the α subunit of the heterotrimeric complex (3–4). Both GTP-bound Gα in the active form and the released Gβγ dimer can then go on to stimulate a number of downstream effectors (5). When the GTP on Gα is hydrolyzed to GDP (6) the original receptor is restored (1).<ref>{{Cite book|title=Progress in Molecular Biology and Translational Science|volume = 133|last1=Stewart|first1=Adele|last2=Fisher|first2=Rory A.|year=2015|publisher=Elsevier|isbn=9780128029381|pages=1–11|doi=10.1016/bs.pmbts.2015.03.002|pmid = 26123299}}</ref>]]
Receptor-activated G proteins are bound to the inner surface of the [[cell membrane]]. They consist of the G<sub>α</sub> and the tightly associated G<sub>βγ</sub> subunits. 
There are four main families of G<sub>α</sub> subunits: Gα<sub>s</sub> (G stimulatory), Gα<sub>i</sub> (G inhibitory), Gα<sub>q/11</sub>, and Gα<sub>12/13</sub>.<ref>{{cite journal |last1=Syrovatkina |first1=Viktoriya |last2=Alegre |first2=Kamela O. |last3=Dey |first3=Raja |last4=Huang |first4=Xin-Yun |title=Regulation, Signaling, and Physiological Functions of G-Proteins |journal=Journal of Molecular Biology |date=25 September 2016 |volume=428 |issue=19 |pages=3850–3868 |doi=10.1016/j.jmb.2016.08.002 |pmid=27515397 |pmc=5023507 |language=en |issn=0022-2836}}</ref><ref>{{cite web |title=InterPro |url=https://www.ebi.ac.uk/interpro/entry/InterPro/IPR001019/ |website=www.ebi.ac.uk |access-date=25 May 2023}}</ref> They behave differently in the recognition of the effector molecule, but share a similar mechanism of activation.

==== Activation ====
When a [[ligand (biochemistry)|ligand]] activates the [[G protein-coupled receptor]], it induces a conformational change in the receptor that allows the receptor to function as a [[guanine nucleotide exchange factor]] (GEF) that exchanges GDP for GTP. The GTP (or GDP) is bound to the G<sub>α</sub> subunit in the traditional view of heterotrimeric GPCR activation. This exchange triggers the dissociation of the G<sub>α</sub> subunit (which is bound to GTP) from the G<sub>βγ</sub> dimer and the receptor as a whole. However, models which suggest molecular rearrangement, reorganization, and pre-complexing of effector molecules are beginning to be accepted.<ref name="Kou Qin">{{cite journal | vauthors = Qin K, Dong C, Wu G, Lambert NA | title = Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers | journal = Nature Chemical Biology | volume = 7 | issue = 10 | pages = 740–7 | date = August 2011 | pmid = 21873996 | pmc = 3177959 | doi = 10.1038/nchembio.642 }}</ref><ref name="pmid17095603">{{cite journal | vauthors = Digby GJ, Lober RM, Sethi PR, Lambert NA | title = Some G protein heterotrimers physically dissociate in living cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 47 | pages = 17789–94 | date = November 2006 | pmid = 17095603 | pmc = 1693825 | doi = 10.1073/pnas.0607116103 | bibcode = 2006PNAS..10317789D | doi-access = free }}</ref><ref name="pmid19089952">{{cite journal | vauthors = Khafizov K, Lattanzi G, Carloni P | title = G protein inactive and active forms investigated by simulation methods | journal = Proteins | volume = 75 | issue = 4 | pages = 919–30 | date = June 2009 | pmid = 19089952 | doi = 10.1002/prot.22303 | s2cid = 23909821 }}</ref> Both G<sub>α</sub>-GTP and G<sub>βγ</sub> can then activate different ''signaling cascades'' (or ''[[second messenger]] pathways'') and effector proteins, while the receptor is able to activate the next G protein.<ref name="pmid20348012">{{cite journal | vauthors = Yuen JW, Poon LS, Chan AS, Yu FW, Lo RK, Wong YH | title = Activation of STAT3 by specific Galpha subunits and multiple Gbetagamma dimers | journal = The International Journal of Biochemistry & Cell Biology | volume = 42 | issue = 6 | pages = 1052–9 | date = June 2010 | pmid = 20348012 | doi = 10.1016/j.biocel.2010.03.017 }}</ref>

==== Termination ====
The G<sub>α</sub> subunit will eventually [[Hydrolysis|hydrolyze]] the attached GTP to GDP by its inherent [[enzyme|enzymatic]] activity, allowing it to re-associate with G<sub>βγ</sub> and starting a new cycle. A group of proteins called [[Regulator of G protein signalling]] (RGSs), act as [[GTPase-activating proteins]] (GAPs), are specific for G<sub>α</sub> subunits. These proteins accelerate the hydrolysis of GTP to GDP, thus terminating the transduced signal. In some cases, the effector ''itself'' may possess intrinsic GAP activity, which then can help deactivate the pathway. This is true in the case of [[phospholipase C]]-beta, which possesses GAP activity within its [[C-terminus|C-terminal]] region. This is an alternate form of regulation for the G<sub>α</sub> subunit. Such G<sub>α</sub> GAPs do not have catalytic residues (specific amino acid sequences) to activate the G<sub>α</sub> protein. They work instead by lowering the required [[activation energy]] for the reaction to take place.<ref>{{cite book | vauthors = Sprang SR, Chen Z, Du X | title = Structural basis of effector regulation and signal termination in heterotrimeric Galpha proteins | chapter = Structural Basis of Effector Regulation and Signal Termination in Heterotrimeric Gα Proteins | volume = 74 | pages = 1–65 | year = 2007 | pmid = 17854654 | doi = 10.1016/S0065-3233(07)74001-9 | isbn = 978-0-12-034288-4 | series = Advances in Protein Chemistry }}</ref>

====Specific mechanisms====

=====G<sub>αs</sub>=====
'''[[Gαs|G<sub>αs</sub>]]''' activates the [[cAMP-dependent pathway]] by stimulating the production of [[cyclic AMP]] (cAMP) from [[adenosine triphosphate|ATP]]. This is accomplished by direct stimulation of the membrane-associated enzyme [[adenylate cyclase]]. cAMP can then act as a second messenger that goes on to interact with and activate [[protein kinase A]] (PKA). PKA can phosphorylate a myriad downstream targets.

The [[cAMP-dependent pathway]] is used as a signal transduction pathway for many hormones including:

* [[Antidiuretic hormone|ADH]] – Promotes water retention by the [[kidneys]] (created by the [[magnocellular neurosecretory cell]]s of the [[posterior pituitary]])
* [[GHRH]] – Stimulates the synthesis and release of GH ([[somatotropic cell]]s of the [[anterior pituitary]])
* [[GHIH]] – Inhibits the synthesis and release of GH (somatotropic cells of anterior pituitary)
* [[Corticotropin-releasing hormone|CRH]] – Stimulates the synthesis and release of ACTH (anterior pituitary)
* [[ACTH]] – Stimulates the synthesis and release of [[cortisol]] ([[zona fasciculata]] of the [[adrenal cortex]] in the adrenal glands)
* [[Thyroid-stimulating hormone|TSH]] – Stimulates the synthesis and release of a majority of [[Thyroxine|T4]] (thyroid gland)
* [[Luteinizing hormone|LH]] – Stimulates follicular maturation and ovulation in women; or testosterone production and spermatogenesis in men
* [[Follicle stimulating hormone|FSH]] – Stimulates follicular development in women; or [[spermatogenesis]] in men
* [[Parathyroid hormone|PTH]] – Increases [[blood calcium]] levels.  This is accomplished via the [[parathyroid hormone 1 receptor]] (PTH1) in the kidneys and bones, or via the [[parathyroid hormone 2 receptor]] (PTH2) in the central nervous system and brain, as well as the bones and kidneys.
* [[Calcitonin]] – Decreases blood calcium levels (via the [[calcitonin receptor]] in the intestines, bones, kidneys, and brain)
* [[Glucagon]] – Stimulates [[glycogen]] breakdown in the liver
* [[human chorionic gonadotropin|hCG]] – Promotes cellular differentiation, and is potentially involved in [[apoptosis]].<ref>{{cite journal | vauthors = Cole LA | title = Biological functions of hCG and hCG-related molecules | journal = Reproductive Biology and Endocrinology | volume = 8 | issue = 1 | pages = 102 | date = August 2010 | pmid = 20735820 | pmc = 2936313 | doi = 10.1186/1477-7827-8-102 | doi-access = free }}</ref>
* [[Epinephrine]] – released by the ''[[adrenal medulla]]'' during the fasting state, when body is under metabolic duress.  It stimulates [[glycogenolysis]], in addition to the actions of [[glucagon]].

=====G<sub>αi</sub>=====
'''[[Gαi|G<sub>αi</sub>]]''' inhibits the production of cAMP from ATP.
e.g. somatostatin, prostaglandins

=====G<sub>αq/11</sub>=====
'''[[Gαq|G<sub>αq/11</sub>]]''' stimulates the membrane-bound [[phospholipase C]] beta, which then cleaves [[phosphatidylinositol 4,5-bisphosphate]] (PIP<sub>2</sub>) into two second messengers, [[inositol trisphosphate]] (IP<sub>3</sub>) and [[diacylglycerol]] (DAG). IP<sub>3</sub> induces calcium release from the [[endoplasmic reticulum]]. DAG activates [[protein kinase C]].
The Inositol Phospholipid Dependent Pathway is used as a signal transduction pathway for many hormones including:
* Epinephrine
* ADH ([[Vasopressin]]/AVP) – Induces the synthesis and release of [[glucocorticoid]]s ([[Zona fasciculata]] of [[adrenal cortex]]); Induces vasoconstriction (V1 Cells of [[Posterior pituitary]])
* [[Thyrotropin-releasing hormone|TRH]] – Induces the synthesis and release of TSH ([[Anterior pituitary gland]])
* TSH – Induces the synthesis and release of a small amount of T4 ([[Thyroid Gland]])
* [[Angiotensin#Angiotensin II|Angiotensin II]] – Induces Aldosterone synthesis and release ([[zona glomerulosa]] of adrenal cortex in kidney)
* [[Gonadotropin-releasing hormone|GnRH]] – Induces the synthesis and release of FSH and LH (Anterior Pituitary)

=====G<sub>α12/13</sub>=====
*'''[[G12/G13 alpha subunits|G<sub>α12/13</sub>]]''' are involved in Rho family GTPase signaling (see [[Rho family of GTPases]]).  This is through the RhoGEF superfamily involving the [[RhoGEF domain]] of the proteins' structures). These are involved in control of cell cytoskeleton remodeling, and thus in regulating cell migration.

=====G<sub>β</sub>, G<sub>γ</sub>=====
*The '''[[Beta-gamma complex|G<sub>βγ</sub>]]''' complexes sometimes also have active functions. Examples include coupling to and activating [[G protein-coupled inwardly-rectifying potassium channel]]s.

===Small GTPases===
{{Main|Small GTPase}}

Small GTPases, also known as small G-proteins, bind GTP and GDP likewise, and are involved in [[signal transduction]]. These proteins are homologous to the alpha (α) subunit found in heterotrimers, but exist as monomers.  They are small (20-kDa to 25-kDa) [[protein]]s that bind to guanosine triphosphate ([[Guanosine triphosphate|GTP]]). This family of proteins is homologous to the [[Ras subfamily|Ras GTPases]] and is also called the Ras superfamily [[GTPase]]s.