Editing G protein-coupled receptor (section)

==Mechanism==
[[File:GPCR activation.jpg|right|thumb|400px|Cartoon depicting the basic concept of GPCR conformational activation. Ligand binding disrupts an ionic lock between the E/DRY motif of TM-3 and acidic residues of TM-6. As a result, the GPCR reorganizes to allow activation of G-alpha proteins. The "side perspective" is a view from above and to the side of the GPCR as it is set in the plasma membrane (the membrane lipids have been omitted for clarity). The incorrectly labelled "intracellular perspective" shows an extracellular view looking down at the plasma membrane from outside the cell.<ref name="pmid20019124">{{cite journal | vauthors = Millar RP, Newton CL | title = The year in G protein-coupled receptor research | journal = Molecular Endocrinology | volume = 24 | issue = 1 | pages = 261–74 | date = January 2010 | pmid = 20019124 | pmc = 5428143 | doi = 10.1210/me.2009-0473 }}</ref>]]

The G protein-coupled receptor is activated by an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a [[G protein]]. Further effect depends on the type of G protein. G proteins are subsequently inactivated by GTPase activating proteins, known as [[regulator of G protein signaling|RGS proteins]].{{cn|date=April 2025}}

===Ligand binding===
GPCRs include one or more receptors for the following ligands:
sensory signal mediators (e.g., light and [[olfactory]] stimulatory molecules);
[[adenosine]], [[bombesin]], [[bradykinin]], [[endothelin]], γ-aminobutyric acid ([[gamma-aminobutyric acid|GABA]]), hepatocyte growth factor ([[hepatocyte growth factor|HGF]]), [[melanocortin]]s, [[neuropeptide Y]], [[opioid]] peptides, [[opsin]]s, [[somatostatin]], [[growth hormone|GH]], [[tachykinins]], members of the [[vasoactive intestinal peptide]] family, and [[vasopressin]];
[[biogenic amine]]s (e.g., [[dopamine]], [[epinephrine]], [[norepinephrine]], [[histamine]], [[serotonin]], and [[melatonin]]);
[[glutamate]] ([[metabotropic]] effect);
[[glucagon]];
[[acetylcholine]] ([[muscarinic]] effect);
[[chemokines]];
[[lipid]] mediators of [[inflammation]] (e.g., [[prostaglandins]], [[prostanoid]]s, [[platelet-activating factor]], and [[leukotrienes]]);
peptide hormones (e.g., [[calcitonin]], C5a [[anaphylatoxin]], [[follicle-stimulating hormone]] [FSH], [[gonadotropin-releasing hormone]] [GnRH], [[neurokinin]], [[thyrotropin-releasing hormone]] [TRH], and [[oxytocin]]);
and [[endocannabinoid]]s.

GPCRs that act as receptors for stimuli that have not yet been identified are known as [[orphan receptor]]s.{{cn|date=April 2025}}

However, in contrast to other types of receptors that have been studied, wherein ligands bind externally to the membrane, the [[ligand (biochemistry)|ligand]]s of GPCRs typically bind within the transmembrane domain. However, [[protease-activated receptor]]s are activated by cleavage of part of their extracellular domain.<ref name="pmid12970120">{{cite journal | vauthors = Brass LF | s2cid = 22279536 | title = Thrombin and platelet activation | journal = Chest | volume = 124 | issue = 3 Suppl | pages = 18S–25S | date = September 2003 | pmid = 12970120 | doi = 10.1378/chest.124.3_suppl.18S }}</ref>

=== Conformational change ===

[[File:Beta2Receptor-with-Gs.png|right|thumb|300px|Crystal structure of activated beta-2 adrenergic receptor in complex with G<sub>s</sub>([[w:Protein Data Bank|PDB]] entry [https://web.archive.org/web/20180128134132/https://www.rcsb.org/structure/3SN6 3SN6]). The receptor is colored red, Gα green, Gβ cyan, and Gγ yellow. The C-terminus of Gα is located in a cavity created by an outward movement of the cytoplasmic parts of TM5 and 6.]]

The [[signal transduction|transduction of the signal]] through the membrane by the receptor is not completely understood. It is known that in the inactive state, the GPCR is bound to a [[heterotrimeric G protein]] complex. Binding of an agonist to the GPCR results in a [[conformational change]] in the receptor that is transmitted to the bound G<sub>α</sub> subunit of the heterotrimeric G protein via [[protein dynamics#Global flexibility: multiple domains|protein domain dynamics]]. The activated G<sub>α</sub> subunit exchanges [[guanosine triphosphate|GTP]] in place of [[guanosine diphosphate|GDP]] which in turn triggers the dissociation of G<sub>α</sub> subunit from the G<sub>βγ</sub> dimer and from the receptor. The dissociated G<sub>α</sub> and G<sub>βγ</sub> subunits interact with other intracellular proteins to continue the signal transduction cascade while the freed GPCR is able to rebind to another heterotrimeric G protein to form a new complex that is ready to initiate another round of signal transduction.<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>

It is believed that a receptor molecule exists in a conformational [[dynamic equilibrium|equilibrium]] between active and inactive biophysical states.<ref>{{cite journal |vauthors=Rubenstein LA, Lanzara RG |title=Activation of G protein-coupled receptors entails cysteine modulation of agonist binding |journal= Journal of Molecular Structure: Theochem|year=1998 |volume=430 |pages=57–71 |url=https://cogprints.org/4095/ |doi=10.1016/S0166-1280(98)90217-2 |access-date=14 January 2006 |archive-date=16 May 2011 |archive-url=https://web.archive.org/web/20110516061030/https://cogprints.org/4095/ |url-status=live }}</ref> The binding of ligands to the receptor may shift the equilibrium toward the active receptor states. Three types of ligands exist: Agonists are ligands that shift the equilibrium in favour of active states; [[inverse agonist]]s are ligands that shift the equilibrium in favour of inactive states; and neutral antagonists are ligands that do not affect the equilibrium. It is not yet known how exactly the active and inactive states differ from each other.{{cn|date=April 2025}}

===G-protein activation/deactivation cycle===
[[File:GPCR cycle.jpg|thumb|500px|Cartoon depicting the heterotrimeric G-protein activation/deactivation cycle in the context of GPCR signaling]]
{{See also|G protein}}
When the receptor is inactive, the [[guanine nucleotide exchange factor|GEF]] domain may be bound to an also inactive α-subunit of a [[heterotrimeric G-protein]]. These "G-proteins" are a [[protein trimer|trimer]] of α, β, and γ subunits (known as Gα, Gβ, and Gγ, respectively) that is rendered inactive when reversibly bound to [[Guanosine diphosphate]] (GDP) (or, alternatively, no guanine nucleotide) but active when bound to [[guanosine triphosphate]] (GTP). Upon receptor activation, the GEF domain, in turn, [[allosterically]] activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit. The cell maintains a 10:1 ratio of cytosolic GTP:GDP so exchange for GTP is ensured. At this point, the subunits of the G-protein dissociate from the receptor, as well as each other, to yield a Gα-GTP [[monomer]] and a tightly interacting [[G beta-gamma complex|Gβγ dimer]], which are now free to modulate the activity of other intracellular proteins. The extent to which they may [[diffuse]], however, is limited due to the [[palmitoylation]] of Gα and the presence of an [[isoprenoid]] moiety that has been [[covalent bond|covalently]] added to the C-termini of Gγ.{{cn|date=April 2025}}

Because Gα also has slow [[GTP-ase|GTP→GDP hydrolysis]] capability, the inactive form of the α-subunit (Gα-GDP) is eventually regenerated, thus allowing reassociation with a Gβγ dimer to form the "resting" G-protein, which can again bind to a GPCR and await activation. The rate of GTP hydrolysis is often accelerated due to the actions of another family of allosteric modulating proteins called [[regulator of G protein signaling|regulators of G-protein signaling]], or RGS proteins, which are a type of [[GTPase-activating protein]], or GAP. In fact, many of the primary [[Effector (biology)|effector]] proteins (e.g., [[adenylate cyclase]]s) that become activated/inactivated upon interaction with Gα-GTP also have GAP activity. Thus, even at this early stage in the process, GPCR-initiated signaling has the capacity for self-termination.{{cn|date=April 2025}}

===Crosstalk===
[[File:GPCR and itegrin signaling diagram.png|thumb|Proposed downstream interactions between [[integrin]] signaling and GPCRs. Integrins are shown elevating Ca<sup>2+</sup> and phosphorylating FAK, which is weakening GPCR signaling.]]
GPCRs downstream signals have been shown to possibly interact with [[integrin]] signals, such as [[PTK2|FAK]].<ref>{{cite journal | vauthors = Teoh CM, Tam JK, Tran T | title = Integrin and GPCR Crosstalk in the Regulation of ASM Contraction Signaling in Asthma | journal = Journal of Allergy | volume = 2012 | pages = 341282 | year = 2012 | pmid = 23056062 | pmc = 3465959 | doi = 10.1155/2012/341282 | doi-access = free }}</ref> Integrin signaling will phosphorylate FAK, which can then decrease GPCR G<sub>αs</sub> activity.