Fig. 1.

The “classical” model of arrestin-mediated GPCR desensitization. The agonist-activated receptor activates cognate heterotrimeric G proteins that subsequently stimulate various signaling cascades increasing the activity of protein kinases PKA, PKC, etc. Active receptor is specifically phosphorylated by GRKs. Arrestin binds the active phosphoreceptor with high affinity, precluding further G protein activation. Arrestin serves as an adaptor linking the receptor to the internalization machinery of the coated pit (clathrin, adaptor complex AP-2), facilitating receptor internalization. Low pH in the endosome promotes agonist dissociation, which facilitates the release of arrestin, whereupon the receptor can be dephosphorylated and recycled back to the plasma membrane (resensitization). Alternatively, the receptor can be transported to lysosomes and destroyed (down-regulation).