Desensitization of G protein-coupled receptors and neuronal functions

被引:646
作者
Gainetdinov, RR [1 ]
Premont, RT
Bohn, LM
Lefkowitz, RJ
Caron, MG
机构
[1] Duke Univ, Med Ctr, Howard Hughes Med Inst Labs, Dept Cell Biol, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Howard Hughes Med Inst Labs, Dept Biochem, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Howard Hughes Med Inst Labs, Dept Med, Durham, NC 27710 USA
关键词
sensitization; tolerance; opiates; antinociception; psychostimulants;
D O I
10.1146/annurev.neuro.27.070203.144206
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modem 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 betaarrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or betaarrestins 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 betaarrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules m certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the utility of a pharmacological strategy aimed at targeting this GPCR desensitization machinery to regulate brain functions can be envisaged.
引用
收藏
页码:107 / 144
页数:38
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