Ahmed Mohamed Rafiuddin, Gurevich Vsevolod V, Dalby Kevin N, Benovic Jeffrey L, Gurevich Eugenia V
Department of Pharmacology, Vanderbilt University Medical Center, Preston Research Building, Room 422, Nashville, TN 37232, USA.
J Pharmacol Exp Ther. 2008 Apr;325(1):276-83. doi: 10.1124/jpet.107.131987. Epub 2008 Jan 4.
Dopamine and other G protein-coupled receptors (GPCRs) represent the major target of antipsychotic drugs. GPCRs undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Arrestins and GRKs are major regulators of GPCR signaling. We elucidated changes in expression of two arrestins and four GRKs following chronic (21 days) treatment with haloperidol (1 mg/kg i.p.) or clozapine (20 mg/kg i.p.) 2 or 24 h after the last injection in 11 brain regions. Haloperidol decreased GRK3 in ventrolateral caudate-putamen and transiently down-regulated GRK5 in globus pallidus and caudal caudate-putamen. Clozapine also caused a short-term suppression of the GRK5 expression in the caudal caudate-putamen and globus pallidus, but, unlike haloperidol, elevated GRK5 in the caudal caudate-putamen after 24 h. Unlike haloperidol, clozapine decreased arrestin2 and GRK3 in hippocampus and GRK3 in globus pallidus but increased arrestin2 in the core of nucleus accumbens and ventrolateral caudate-putamen and GRK2 in prefrontal cortex. Clozapine, but not haloperidol, induced long-term activation of extracellular signal-regulated kinase (ERK) 2 in ventrolateral caudate-putamen and transient in prefrontal cortex. The data demonstrate that haloperidol and clozapine differentially affect the expression of arrestins and GRKs and ERK activity, which may play a role in determining their clinical profile.
多巴胺和其他G蛋白偶联受体（GPCRs）是抗精神病药物的主要靶点。GPCRs通过G蛋白偶联受体激酶（GRKs）的激活依赖性磷酸化，随后与抑制蛋白结合而发生脱敏。抑制蛋白和GRKs是GPCR信号传导的主要调节因子。我们阐明了在11个脑区末次注射氟哌啶醇（1 mg/kg腹腔注射）或氯氮平（20 mg/kg腹腔注射）21天慢性治疗后2小时或24小时，两种抑制蛋白和四种GRKs的表达变化。氟哌啶醇降低了腹外侧尾状核-壳核中的GRK3，并短暂下调了苍白球和尾侧尾状核-壳核中的GRK5。氯氮平也导致尾侧尾状核-壳核和苍白球中GRK5表达的短期抑制，但与氟哌啶醇不同的是，24小时后尾侧尾状核-壳核中的GRK5升高。与氟哌啶醇不同，氯氮平降低了海马中的抑制蛋白2和GRK3以及苍白球中的GRK3，但增加了伏隔核核心和腹外侧尾状核-壳核中的抑制蛋白2以及前额叶皮质中的GRK2。氯氮平而非氟哌啶醇诱导了腹外侧尾状核-壳核中细胞外信号调节激酶（ERK）2的长期激活以及前额叶皮质中的短暂激活。数据表明，氟哌啶醇和氯氮平对抑制蛋白和GRKs的表达以及ERK活性有不同影响，这可能在决定它们的临床特征中起作用。
