Editing G protein-coupled receptor (section)

===Mechanisms of GPCR signal termination===

As mentioned above, G-proteins may terminate their own activation due to their intrinsic [[GTPase|GTP→GDP hydrolysis]] capability. However, this reaction proceeds at a slow [[rate constant|rate]] (≈0.02 times/sec) and, thus, it would take around 50 seconds for any single G-protein to deactivate if other factors did not come into play. Indeed, there are around 30 [[protein isoform|isoforms]] of [[regulator of G protein signaling|RGS proteins]] that, when bound to Gα through their [[GTPase activating protein|GAP domain]], accelerate the hydrolysis rate to ≈30 times/sec. This 1500-fold increase in rate allows for the cell to respond to external signals with high speed, as well as spatial [[angular resolution|resolution]] due to limited amount of [[second messenger]] that can be generated and limited distance a G-protein can diffuse in 0.03 seconds. For the most part, the RGS proteins are [[promiscuous]] in their ability to deactivate G-proteins, while which RGS is involved in a given signaling pathway seems more determined by the tissue and GPCR involved than anything else. In addition, RGS proteins have the additional function of increasing the rate of GTP-GDP exchange at GPCRs, (i.e., as a sort of co-GEF) further contributing to the time resolution of GPCR signaling.

In addition, the GPCR may be [[homologous desensitization|desensitized]] itself. This can occur as:

# a direct result of [[receptor theory|ligand occupation]], wherein the change in [[protein conformation|conformation]] allows recruitment of [[G protein-coupled receptor kinase|GPCR-Regulating Kinases]] (GRKs), which go on to [[phosphorylation|phosphorylate]] various [[serine]]/[[threonine]] residues of IL-3 and the [[C-terminal]] tail. Upon GRK phosphorylation, the GPCR's affinity for [[arrestin|β-arrestin]] (β-arrestin-1/2 in most tissues) is increased, at which point β-arrestin may bind and act to both [[sterically]] hinder G-protein coupling as well as initiate the process of [[receptor-mediated endocytosis|receptor internalization]] through [[clathrin-mediated endocytosis]]. Because only the liganded receptor is desensitized by this mechanism, it is called [[homologous desensitization]]
# the affinity for β-arrestin may be increased in a ligand occupation and GRK-independent manner through phosphorylation of different ser/thr sites (but also of IL-3 and the C-terminal tail) by PKC and PKA. These phosphorylations are often sufficient to impair G-protein coupling on their own as well.<ref name="pmid18193069">{{cite journal | vauthors = Tobin AB | title = G-protein-coupled receptor phosphorylation: where, when and by whom | journal = British Journal of Pharmacology | volume = 153 | issue = Suppl 1| pages = S167–76 | date = March 2008 | pmid = 18193069 | pmc = 2268057 | doi = 10.1038/sj.bjp.0707662 }}</ref>
# PKC/PKA may, instead, phosphorylate GRKs, which can also lead to GPCR phosphorylation and β-arrestin binding in an occupation-independent manner. These latter two mechanisms allow for desensitization of one GPCR due to the activities of others, or [[heterologous desensitization]]. GRKs may also have GAP domains and so may contribute to inactivation through non-[[kinase]] mechanisms as well. A combination of these mechanisms may also occur.

Once β-arrestin is bound to a GPCR, it undergoes a conformational change allowing it to serve as a scaffolding protein for an adaptor complex termed [[AP2 adaptors|AP-2]], which in turn recruits another protein called [[clathrin]]. If enough receptors in the local area recruit clathrin in this manner, they aggregate and the [[plasma membrane|membrane]] buds inwardly as a result of interactions between the molecules of clathrin, in a process called [[opsonization]]. Once the pit has been pinched off the [[plasma membrane]] due to the actions of two other proteins called [[amphiphysin]] and [[dynamin]], it is now an [[endocytosis|endocytic]] [[vesicle (biology)|vesicle]]. At this point, the adapter molecules and clathrin have [[dissociated]], and the receptor is either [[protein targeting|trafficked]] back to the plasma membrane or targeted to [[lysosome]]s for [[proteolysis|degradation]].

At any point in this process, the β-arrestins may also recruit other proteins—such as the [[non-receptor tyrosine kinase]] (nRTK), [[Src (gene)|c-SRC]]—which may activate [[extracellular signal-regulated kinases|ERK1/2]], or other [[mitogen-activated protein kinase]] (MAPK) signaling through, for example, phosphorylation of the [[small GTPase]], [[Ras subfamily|Ras]], or recruit the proteins of the [[MAPK/ERK pathway|ERK cascade]] directly (i.e., [[Raf-1]], [[mitogen-activated protein kinase kinase|MEK]], ERK-1/2) at which point signaling is initiated due to their close proximity to one another. Another target of c-SRC are the dynamin molecules involved in endocytosis. Dynamins [[polymerization|polymerize]] around the neck of an incoming vesicle, and their phosphorylation by c-SRC provides the energy necessary for the conformational change allowing the final "pinching off" from the membrane.