Transcript PPT
The involvement of G proteins and regulators of receptor–G protein coupling in the pathophysiology, diagnosis and treatment of mood disorders Pathophysiology:病理生理学 Mood disorder • 单极情绪紊乱 如抑郁症 ，狂躁症等 • 多极情绪紊乱（bipolar mood disorder ） 躁狂发作(manicepisode)与忧郁发作 (depressiveepisode)交互或混合地出现 Biochemical research in mood disorders has focused, along the cascade of events involved in signal transduction, from studies at the level of the monoamine neurotransmitter to the level of the neurotransmitter receptors, and lately to information transduction mechanisms beyond receptors, involving the coupling of receptors with signal transducers. Research level • Momoamine neurotrotransmitter 第一信 使水平 • Neurotrotransmitter recepter 膜受体水平 • information transduction mechanisms beyond receptors 第二信使水平 The “pharmacological bridge” approach to the construction of pathogenic hypotheses for mood disorders The pharmacological bridge approach to the construction of biological hypotheses for the pathogenesis of mental disorders is trying to induce from knowledge and hypotheses concerning the biochemical mechanisms of action of neuro-psychiatric medications to pathogenic and pathophysiological hypotheses,e.g. dopamine ------------- schizophrenia monoamine -------------mood disorders. 治疗药物——降低生物胺水平——降血压—— 抗狂躁;治疗药物——提高生物胺的功能性— —抗抑郁 • First,reserpine(利血平),a medication that decreases blood pressure by depleting biogenic amine stores, was known to precipitate clinical depression in some patients • Second, antidepressant medications（抗抑 郁药物）, which alleviate clinical depression, were found to raise the functional capacity of the biogenic amines in the brain. monoamine oxidase A (MAO-A) A mitochondrial enzyme that plays an important role in degradative deamination(去胺化) of several different amines, including serotonin（血液复合胺）, norepinephrine（去甲肾上腺素） and dopamine The involvement of receptor signal transducers-G proteins in the pathophysiology and treatment of mood disorders Lithium (Li) inhibition of beta-adrenergic receptor coupled G proteins’ function was suggested as a single molecular site for antidepressant therapeutic effects of this ion . Lithium’s molecular mechanism of interaction with G proteins was found to involve competition with magnesium（Mg） ions on magnesium low-affinity sites (Mg低亲和位 点)essential for guanine nucleotide （鸟苷酸） exchange on these proteins （activation of G proteins by guanine nucleotides . (G protion level,mRNA level) 鸟苷酸结合蛋白（guanine nucleotidebinding regulatory protein），简称G蛋白 . 第二信使学说，其主要内容包括：①激素 是第一信使，它可与靶细胞膜上具有立 体构型的专一性受体结合；②激素与受 体结合后，激活漠上的腺苷酸环化酶系 统；③在mg2+存在的条件下，腺苷酸环 化酶促使ATP转变为cAMP，cAMP是第 二信使，信息由第一信使传递给第二信 使；④cAMP是使无活性的蛋白激酶 （PKA）激活。 Subsequent studies have shown that lithium decreased the levels of mRNA for the alpha subunits of Gs, Gi and Go proteins . Measuring G protein function through agonist (serotonin血液中的复合胺) enhanced guanine nucleotide binding in rat cortical（脑皮层） membranes, lithium was found to interfere with receptor–G protein (Gs, Gi and Go) coupling via a magnesium-sensitive mechanism . G protein-coupled receptor kinases (GRKs) Using a functional genomic approach a series of candidate genes involved in the pathogenesis of mood disorders was identified including G protein-coupled receptor kinase 3 (GRK3), which was also found to be decreased in lymphoblastoid cell（淋巴母细胞） lines from a subset of bipolar patients . More recently a single nucleotide polymorphism (SNP单核苷多态现象) in the promoter region of GRK3 was found to be associated with bipolar disorder. The findings concerning GRK3 gene are in accord with evidence from genomewide linkage survey suggesting that the chromosome 22q12 (22号染色 体长臂1区2带)region contains a susceptibility locus （易感情化区） for bipolar disorder. 单核苷酸多态性(SNP) 是指在基因组上单个核苷酸的变异,包括置换、 颠换、缺失和插入。从理论上来看每一个SNP 位点都可以有4 种不同的变异形式,但实际上发 生的只有两种,即转换和颠换,二者之比为2 :1。 SNP 在CG序列上出现最为频繁,而且多是C转换 为T ,原因是CG中的C 常为甲基化的,自发地脱 氨后即成为胸腺嘧啶。一般而言,SNP 是指变异 频率大于1 %的单核苷酸变异。在人类基因组 中大概每1000 个碱基就有一个SNP ,人类基因 组上的SNP 总量大概是3 ×106 个 。 Membrane-associated GRK 2/3 was found to be increased in specimens of postmortem prefrontal cortices collected from depressed patients.Acute treatment (1–6 h) with the tricyclic antidepressant desipramine（脱甲丙咪嗪，抗抑郁药) , increased membrane-associated GRK 2/3 in rat brain. This effect vanished（消失） with a prolonged desipramine exposure（延长处理时间） (24h–14days) . Major depression was found to be associated with reduced platelet（血小板） GRK 2, while treatment with mirtazapine（米尔 塔扎平，抗抑郁药) reversed（颠倒） this abnormality .