Editing G protein-coupled receptor (section)

===Phosphorylation by GRKs===

The [[G protein-coupled receptor kinases]] (GRKs) are protein kinases that phosphorylate only active GPCRs.<ref name="Trimarco2013">{{cite journal | vauthors = Santulli G, Trimarco B, Iaccarino G | title = G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms | journal = High Blood Pressure & Cardiovascular Prevention | volume = 20 | issue = 1 | pages = 5–12 | date = March 2013 | pmid = 23532739 | doi = 10.1007/s40292-013-0001-8 | s2cid = 45674941 }}</ref> G-protein-coupled receptor kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR) signaling. They constitute a family of seven mammalian serine-threonine protein kinases that phosphorylate agonist-bound receptor. GRKs-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization. Activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins.<ref name="pmid14499340">{{cite journal | vauthors = Penela P, Ribas C, Mayor F | title = Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases | journal = Cellular Signalling | volume = 15 | issue = 11 | pages = 973–81 | date = November 2003 | pmid = 14499340 | doi = 10.1016/S0898-6568(03)00099-8 }}</ref>

Phosphorylation of the receptor can have two consequences:

# ''Translocation'': The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment<ref name="pmid8995214">{{cite journal | vauthors = Krueger KM, Daaka Y, Pitcher JA, Lefkowitz RJ | title = The role of sequestration in G protein-coupled receptor resensitization. Regulation of beta2-adrenergic receptor dephosphorylation by vesicular acidification | journal = The Journal of Biological Chemistry | volume = 272 | issue = 1 | pages = 5–8 | date = January 1997 | pmid = 8995214 | doi = 10.1074/jbc.272.1.5 | doi-access = free }}</ref> and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysozomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depending on the internalised vesicle's subcellular localisation.<ref name="pmid14744258"/>
# ''[[Arrestin]] linking'': The phosphorylated receptor can be linked to ''arrestin'' molecules that prevent it from binding (and activating) G proteins, in effect switching it off for a short period of time. This mechanism is used, for example, with [[rhodopsin]] in [[retina]] cells to compensate for exposure to bright light. In many cases, arrestin's binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β<sub>2</sub>-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus, the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β<sub>2</sub>-adrenoreceptors.<ref name="pmid10770944">{{cite journal | vauthors = Laporte SA, Oakley RH, Holt JA, Barak LS, Caron MG | title = The interaction of beta-arrestin with the AP-2 adaptor is required for the clustering of beta 2-adrenergic receptor into clathrin-coated pits | journal = The Journal of Biological Chemistry | volume = 275 | issue = 30 | pages = 23120–6 | date = July 2000 | pmid = 10770944 | doi = 10.1074/jbc.M002581200 | doi-access = free }}</ref><ref name="pmid10097102">{{cite journal | vauthors = Laporte SA, Oakley RH, Zhang J, Holt JA, Ferguson SS, Caron MG, Barak LS | title = The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 7 | pages = 3712–7 | date = March 1999 | pmid = 10097102 | pmc = 22359 | doi = 10.1073/pnas.96.7.3712 | bibcode = 1999PNAS...96.3712L | doi-access = free }}</ref>