Desensitization of G protein-coupled receptors and neuronal functions

Annual Review of Neuroscience
Raul R GainetdinovMarc G Caron

Abstract

G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein-coupled receptor kinases (GRKs). Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways. Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and beta arrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or beta arrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and mu-opioid receptor regulation of locomotion and analgesia. An important and specific role of GRKs and beta arrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in cert...Continue Reading

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Methods Mentioned

BETA
nucleotide exchange
GTPase
transgenic

Related Concepts

Analeptics
Brain
Intropin
Neurons
Phosphorylation
Protein KINASE
Receptors, Opioid, mu
Arrestins
G-Protein-Coupled Receptors

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