Many intracellular and intercellular functions are mediated by G protein-coupled receptors (GPCRs). These signal transduction events can occur through the interactions of GPCRs with G proteins and are triggered by a wide variety of inducers such as hormones, neurotransmitters, chemokines, ions, light, and odors. The activation results in a cascade of signal transduction events such as stimulation or inhibition of adenylyl cyclase and activation of phospholipase C. GPCRs must be inactivated or desensitized; this can take place at the receptor or G protein level, generally through phosphorylation mediated by protein kinase A or C. G protein-coupled kinases (GRKs) can also be involved in the desensitization events.
The interference of arrestin with receptor molecules can prevent further GPCR and G protein interactions. Cellular signal transduction pathways can also be established through the interaction of GPCRs with proteins other than G proteins. For example, tyrosine kinase interactions with the third intracellular domains of GPCRs result in the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade. Moreover, the interaction between p-arrestin and c-Src can facilitate GPCR-dependent activation of the ERK/MAPK
pathway and may play an important role in the GPCR-mediated glucose transport through the stimulation of the GLUT4 glucose transporter. C-terminal interaction of GPCRs with Janus kinases can lead to the activation of the transcription factor STAT (signal transducer and activator of transcription). Arrestin interactions with GPCRs have been shown to be involved in trafficking of GPCRs, that is, their internalization and recycling to the plasma membrane.
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