Once and future signaling: G protein-coupled receptor kinase control of neuronal sensitivity

G protein-coupled receptors (GPCRs) are the most numerous class of cell surface receptor, and substances acting through GPCRs mediate many critical signaling events and physiological processes. GPCR sensitivity and signaling is dynamic, responding rapidly to adjust to changes in the ambient level of stimulation of target cells. One important mediator of such receptor sensitivity is the family of GPCR kinases (GRKs). Like heterotrimeric G proteins, GRKs recognize agonist-bound, activated receptors, and this recognition promotes catalytic activation of GRKs, resulting in the preferential phosphorylation of activated receptors. GRK-phosphorylated receptors are then targeted by arrestin proteins, which bind to phosphorylated receptors. Arrestin-bound receptors are uncoupled from heterotrimeric G proteins, resulting in decreased sensitivity to further receptor stimulation (desensitization). Arrestin-bound receptors are also accelerated into internalization pathways and linked to distinct arrestin-mediated signaling pathways. GRKs thus serve as gatekeepers for receptors, terminating some signaling pathways and initiating others. One major outstanding question concerning GRKs understanding the mechanisms by which any particular receptor subtype (of the 800 or so in the body) is regulated by a specific GRK(s), and the consequences of this specificity. An understanding of this regulatory specificity could allow targeting of GRK function to ameliorate diseases involving GPCR dysregulation.