Once and future signaling

Abstract

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.