<P> 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 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 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 endocytic vesicle . At this point, the adapter molecules and clathrin have dissociated, and the receptor is either trafficked back to the plasma membrane or targeted to lysosomes for degradation . </P> <P> At any point in this process, the β - arrestins may also recruit other proteins--such as the non-receptor tyrosine kinase (nRTK), c - SRC--which may activate ERK1 / 2, or other mitogen - activated protein kinase (MAPK) signaling through, for example, phosphorylation of the small GTP - ase, Ras, or recruit the proteins of the ERK cascade directly (i.e., Raf - 1, 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 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 . </P> <P> Receptor desensitization is mediated through a combination phosphorylation, β - arr binding, and endocytosis as described above . Downregulation occurs when endocytosed receptor is embedded in an endosome that is trafficked to merge with an organelle called a lysosome . Because lysosomal membranes are rich in proton pumps, their interiors have low pH (≈ 4.8 vs. the pH ≈ 7.2 cytosol), which acts to denature the GPCRs . In addition, lysosomes contain many degradative enzymes, including proteases, which can function only at such low pH, and so the peptide bonds joining the residues of the GPCR together may be cleaved . Whether or not a given receptor is trafficked to a lysosome, detained in endosomes, or trafficked back to the plasma membrane depends on a variety of factors, including receptor type and magnitude of the signal . GPCR regulation is additionally mediated by gene transcription factors . These factors can increase or decrease gene transcription and thus increase or decrease the generation of new receptors (up - or down - regulation) that travel to the cell membrane . </P> <P> G - protein - coupled receptor oligomerisation is a widespread phenomenon . One of the best - studied examples is the metabotropic GABA receptor . This so - called constitutive receptor is formed by heterodimerization of GABA R1 and GABA R2 subunits . Expression of the GABA R1 without the GABA R2 in heterologous systems leads to retention of the subunit in the endoplasmic reticulum . Expression of the GABA R2 subunit alone, meanwhile, leads to surface expression of the subunit, although with no functional activity (i.e., the receptor does not bind agonist and cannot initiate a response following exposure to agonist). Expression of the two subunits together leads to plasma membrane expression of functional receptor . It has been shown that GABA R2 binding to GABA R1 causes masking of a retention signal of functional receptors . </P>

Where are g-protein receptors located in the cell