Receptor regulation G protein–coupled receptor

1 receptor regulation

1.1 phosphorylation camp-dependent protein kinases
1.2 phosphorylation grks
1.3 mechanisms of gpcr signal termination
1.4 gpcr cellular regulation

receptor regulation

gpcrs become desensitized when exposed ligand prolonged period of time. there 2 recognized forms of desensitization: 1) homologous desensitization, in activated gpcr downregulated; , 2) heterologous desensitization, wherein activated gpcr causes downregulation of different gpcr. key reaction of downregulation phosphorylation of intracellular (or cytoplasmic) receptor domain protein kinases.

phosphorylation camp-dependent protein kinases

cyclic amp-dependent protein kinases (protein kinase a) activated signal chain coming g protein (that activated receptor) via adenylate cyclase , cyclic amp (camp). in feedback mechanism, these activated kinases phosphorylate receptor. longer receptor remains active more kinases activated , more receptors phosphorylated. in β2-adrenoceptors, phosphorylation results in switching of coupling gs class of g-protein gi class. camp-dependent pka mediated phosphorylation can cause heterologous desensitisation in receptors other activated.

phosphorylation grks

the g protein-coupled receptor kinases (grks) protein kinases phosphorylate active gpcrs. g-protein-coupled receptor kinases (grks) key modulators of g-protein-coupled receptor (gpcr) signaling. constitute family of 7 mammalian serine-threonine protein kinases phosphorylate agonist-bound receptor. grks-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling , desensitization. activity of grks , subcellular targeting tightly regulated interaction receptor domains, g protein subunits, lipids, anchoring proteins , calcium-sensitive proteins.

phosphorylation of receptor can have 2 consequences:

mechanisms of gpcr signal termination

as mentioned above, g-proteins may terminate own activation due intrinsic gtp→gdp hydrolysis capability. however, reaction proceeds @ slow rate (≈.02 times/sec) and, thus, take around 50 seconds single g-protein deactivate if other factors did not come play. indeed, there around 30 isoforms of rgs proteins that, when bound gα through gap domain, accelerate hydrolysis rate ≈30 times/sec. 1500-fold increase in rate allows cell respond external signals high speed, spatial resolution due limited amount of second messenger can generated , limited distance g-protein can diffuse in .03 seconds. part, rgs proteins promiscuous in ability activate g-proteins, while rgs involved in given signaling pathway seems more determined tissue , gpcr involved else. in addition, rgs proteins have additional function of increasing rate of gtp-gdp exchange @ gpcrs, (i.e., sort of co-gef) further contributing time resolution of gpcr signaling.

in addition, gpcr may desensitized itself. can occur as:

once β-arrestin bound gpcr, undergoes conformational change allowing serve scaffolding protein adaptor complex termed ap-2, in turn recruits protein called clathrin. if enough receptors in local area recruit clathrin in manner, aggregate , membrane buds inwardly result of interactions between molecules of clathrin, in process called opsonization. once pit has been pinched off plasma membrane due actions of 2 other proteins called amphiphysin , dynamin, endocytic vesicle. @ point, adapter molecules , clathrin have dissociated, , receptor either trafficked plasma membrane or targeted lysosomes degradation.

at point in process, β-arrestins may recruit other proteins—such non-receptor tyrosine kinase (nrtk), c-src—which may activate erk1/2, or other mitogen-activated protein kinase (mapk) signaling through, example, phosphorylation of small gtp-ase, ras, or recruit proteins of erk cascade directly (i.e., raf-1, mek, erk-1/2) @ point signaling initiated due close proximity 1 another. target of c-src dynamin molecules involved in endocytosis. dynamins polymerize around neck of incoming vesicle, , phosphorylation c-src provides energy necessary conformational change allowing final pinching off membrane.

gpcr cellular regulation

receptor desensitization mediated through combination phosphorylation, β-arr binding, , endocytosis described above. downregulation occurs when endocytosed receptor embedded in endosome trafficked merge organelle called lysosome. because lysosomal membranes rich in proton pumps, interiors have low ph (≈4.8 vs. ph≈7.2 cytosol), acts denature gpcrs. in addition, lysosomes contain many degradative enzymes, including proteases, can function @ such low ph, , peptide bonds joining residues of gpcr may cleaved. whether or not given receptor trafficked lysosome, detained in endosomes, or trafficked plasma membrane depends on variety of factors, including receptor type , magnitude of signal.

gpcr regulation additionally mediated gene transcription factors. these factors can increase or decrease gene transcription , increase or decrease generation of new receptors (up- or down-regulation) travel cell membrane.