1、central nervous system pharmacology中枢神经系统药理（central nervous system pharmacology）神经递质（neurotransmitter）/神经调质（neuromodulator）1. 乙酰胆碱 ACh在中枢分布广泛，中枢发出的运动神经、脑干网状上行激动系统、纹状体、边缘系统和大脑皮质等均有分布。其功能与运动、学习记忆、警觉及内脏活动有关。CNS中M受体主要是M1型受体，Ach兴奋M1受体，造成神经元的慢兴奋现象。少数部位有M2型受体分布。N受体在CNS 的主要功能是在突出前易化其他neurotransmitter的释放。2.
2、去甲肾上腺素 NA在中枢内主要分布在下丘脑、第四脑室极后区及边缘系统、海马等。蓝斑核、延髓及中脑网状结构中NAergic神经元较多。NA可使蓝斑核神经元上的a2受体激活，致K+电导增加形成超极化。而在中枢的大多区域，可激活a1或受体，阻断K+通道，增强传入兴奋的强度。3. 多巴胺 脑内的DA多集中于纹状体、黑质和苍白球。已知的DA通路包括：黑质-纹状体通路、中脑-边缘系统通路、中脑-皮质通路和结节-漏斗通路。它们分别与椎体外系功能、情绪情感、精神理智及内分泌调节有关。现已克隆到5种DA受体，都是G蛋白偶联受体。D1和D5为D1样受体，激活后升高细胞内cAMP水平；D2、D3、D4为D2样受体，
3、激活后降低细胞内cAMP水平。氯丙嗪可阻断D2样受体而产生抗精神病作用。4. 5-羟色胺 CNS的5-羟色胺神经元主要存在于中缝核、神经纤维分布广泛，可投射到纹状体、丘脑、下丘脑、前脑和大脑皮质。其功能与觉醒、睡眠、情绪反应及感觉传递等有关。5-羟色胺受体多而复杂，到目前为止已知有5-HT15-HT7，并存在亚型。除5-HT3为离子通道外，其余多与G蛋白和腺苷酸环化酶或磷脂酶C偶联。5. -氨基丁酸 GABA主要存在于脑内，分布广泛但不均匀，在大脑皮质的浅层含量较高，是中枢抑制性递质。其受体主要有3种，分别为GABA-(A/B/C)。GABA-A为配体-门控Cl-通道，兴奋时Cl-内流增加；G
4、ABA-B为G蛋白偶联受体，兴奋时K+通道电导增加，抑制腺苷酸环化酶和减少Ca+内流；GABA-C功能不详。多种药物可以直接或间接影响GABA受体功能而发挥作用。6. 谷氨酸 管氨酸在脑和脊髓内分布极为广泛，但在大脑皮质和脊髓背侧部分含量相对较高。谷氨酸是中枢的兴奋性递质，作用于皮质神经元和脊髓运动神经元，可引起突触后膜电位（excitatory postsynaptic potential, EPSP），并导致神经元放电。其受体有两种类型：促离子型和促代谢型。前者为G蛋白偶联受体，激活后可使细胞内IP3和DAG增高，cAMP降低，该类受体已鉴定有11种亚型。后者属于配体门控离子通道，有3种类
5、型，分别为海人藻酸（kainate acid,KA）受体、AMPA受体和NMDA受体。NMDA受体是阳离子通道，对Na+、K+和Ca2+通透，可使神经细胞膜去极化，产生慢EPSP。7. 内阿片肽 现已发现与阿片生物碱作用相似的肽类20多种，统称内源性阿片样肽。以确定的阿片受体包括、三种受体，每种受体又有不同的亚型。在丘脑内测、脊髓胶质区、脑室及导水管周围灰质、边缘系统、蓝斑核、孤束核、脑干极后区及迷走神经背核等阿片受体分布密度较高，与疼痛刺激传入、痛觉的整合、情绪及神经活动、呼吸及胃肠活动调节等有关。除上述几种外，还有如甘氨酸、门冬氨酸、腺苷、P物质、组胺、前列腺素等递质或调质对CNS功能进行
6、调节。This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from Bisphenol-A(BPA) exposure, as a pathway of schizophrenia pathogenesis. Epidermal growth factor(EGF) is one of the ErbB receptor ligands implicated in schizophrenia neuropathology as well a
7、s dopaminergic development. Pallidal hyperdopaminergic innervation underlying D2 receptor-dependent behavioral deficits in the schizophrenia animal model established by EGF is elucidated. Model Phosphatidylinositol 3-kinases(PI3K) inhibitor, proved to inhibit Akt activity, block the effect of GABA-B
8、 receptor on the phosphorylation of GSK3 at Ser21/Ser9 sites. GABA-B receptors modulate phosphorylation of GSK-3arpha/beta through a Gi-protein-independent/ beta-arrestin2-dependent pathway. Dopamine D2 receptors can activate the Akt/GSK-3 pathway via G-protein independent/beta-arrestin2-dependent s
9、ignaling. GABA-B and dopamine D2 receptors are Gi/o-coupled receptors. Pertussis toxin(PTX)(200ng/ml,14-18h) uncouples the receptors from Gi/o-protein. Activation of GABA-B receptors increases phosphorylated GSK-3arpha/beta at Ser-21/Ser-9 sites in rat hippocampal slices. Our findings suggest that a
10、ctivation of GABAB inhibits GSK-3 signaling through a -arrestin2-dependent pathway (Figure 5). This pathway involves the upregulation of Akt phosphorylation at Thr-308 and GSK-3/ phosphorylation at Ser-21/Ser-9. As a G-protein coupled receptor (GPCR), the GABAB receptor was thought to exert its effe
11、cts via coupling to pertussis toxin (PTX) sensitive Gi/o proteins, that in turn regulate voltage-gated Ca2+ (CaV)or G protein-gated inwardly rectifying K+ (GIRK) channels, and inhibit adenylyl cyclase. However, our results suggest that activation of GABAB receptor modulates GSK-3 signaling in a G-pr
12、otein independent manner, as PTX failed to block the GABAB receptor effect on GSK-3/ phosphorylation. Interestingly, previous studies have shown that activation of dopamine D2 receptors, which are also Gi/o coupled GPCRs, similarly modulate GSK-3 signaling in a -arrestin dependent pathway. However,
13、the D2 receptor effect on GSK-3 is opposite to the GABAB receptor effect. Activation of D2 receptors leads to -arrestin2 recruitment to the D2 receptors and formation of a -arrestin2-scaffolded protein complex that includes protein phosphatase 2A (PP2A), Akt and GSK-3/. PP2A dephosphorylates Akt at
14、Thr-308 which subsequent activation of GSK-3/ as a consequence of dephosphorylation of GSK-3 at Ser-9 and 21 34. It is worth noting that both receptors modulate GSK-3 signaling by changing the Akt phosphorylation at Thr-308 site and GSK 3/ phosphorylation at Ser-21/Ser-9 sites. The fact that both GA
15、BAB receptor agonists and D2 receptor antagonists exert antipsychotic effects 5,35, together with previous findings that antipsychotics are potent antagonists of the dopamine-induced recruitment of -arrestin2 to the D2 receptors 36, suggests that inhibition of GSK-3 activity may be a molecular mecha
16、nism through which GABAB receptor agonists have antipsychotic effects.Previous studies have suggested that GPCRs can signal without an external chemical trigger, i.e., in a constitutive or spontaneous manner 36. For example, dopamine D5 receptors enhance cAMP accumulation without agonist stimulation
17、 38,39. Consistent with this idea, GABAB receptors also display constitutive activity as we observed a significant decrease of GSK-3/ phosphorylation at Ser-21/Ser-9 sites treated only with the GABAB receptor antagonist CGP52432. The general physiological purpose of such basal activity may be to per
18、mit bi-direction control of receptor activity. With constitutively active pathways, the Output can be either increased or decreased from a mid-range level. GSK-3 is a multi-functional serine/threonine kinase. Its activity is regulated negatively by the phosphorylation of Ser-9 and positively by the
19、phosphorylation of Tyr-216, a GSK-3autophosphorylation site required for regulating its activity. Previous studies have shown that GSK-3 phosphorylsation at Tyr-216 can be prevented by its interaction with DISC1 (Disrupted-in-schizophrenia-1 protein) 40. Thus, it is possible that GABAB receptors inh
20、ibit GSK-3 activity through direct inhibition of GSK-3 phosphorylsation at Tyr-216 site. However, our results indicate that activation of GABAB receptors has no effect on GSK-3phosphorylation at Tyr-216. Interestingly, this data is also consistent with the dopamine D2receptor effect on GSK-3 phsphor
21、ylation as activation of D2 receptor also has no effect onGSK-3 phosphorylation at Tyr-216.Available evidence suggests that antipsychotic drugs exert their antipsychotic effects inschizophrenia through the blockade of dopamine D2 receptors (D2R) or D2R in combination with the serotonin receptor 2A (
22、5-HT2AR) 25,26,41. GABAB receptors and D2R belong to the super family of G-protein coupled receptors (GPCRs) that exert their biological effects via intracellular G protein-coupled signaling cascades 42-45. D2Rs display a complex pattern of signal transduction via their coupling to the Gi/Go protein
23、. Previously, D2Rs were known to stimulate a number of signal transduction pathways including the inhibition of adenylate cyclase activity, PI (phosphatidylinositol) turnover, potentiation of arachidonic acid release, inwardly rectifying K+ and Ca2+ channels and mitogen activated protein kinases 43.
24、 Recently several studies have suggested that D2R can activate the Akt/GSK-3 pathway via - arrestin2-dependent signaling. D2R-mediated Akt/GSK-3 regulation involves the recruitment of -arrestin2 to the D2R and the formation of signaling complexes containing -arrestin2, protein phosphatase 2A (PP2A)
25、and Akt. Formation of this protein complex leads to specific dephosphorylation/inactivation of the serine/threonine kinase Akt on its regulatory Thr-308 residue but not the second regulatory Ser-473 residue 23,27,43 the inactivation of Akt, in response to DA stimulation, leads to a reduction of kina
26、se activity and a concomitant activation of its substrates GSK-3 (Ser-21)/ (Ser-9) since both are negatively regulated by Akt 20. Interestingly, D2R-mediated modulation of GSK-3 signaling targets the same phosphorylation sites as GABAB receptors, but the functional effects are the opposite. The fact
27、 that antipsychotics block D2R and also antagonize the agonist-induced recruitment of -arrestin2 to D2R 29, supports our contention that GABAB receptor-mediated inhibition of GSK-3 signaling may be a target for the development of novel antipsychotic medications.Akt(also known as protein kinase B,PKB
28、) is a relatively new member of the AGC kinase family. Akt又称PKB，即蛋白激酶B，是一种丝氨酸/苏氨酸蛋白激酶，在细胞存活和凋亡中起重要作用。胰岛素等生长和存活因子都可以激活Akt信号途径。Akt的Ser473可以被PDK1磷酸化。PI3K即磷脂酰肌醇-3激酶，PI3K-Akt信号途径是一条经典的信号途径，LY294002等PI3K的抑制剂抑制PI3K时，即可抑制PIP3（磷脂酰肌醇-3磷酸）的生成，阻断了Akt的活化。 Akt能磷酸化一系列蛋白成分，通过多种途径抑制细胞凋亡。3-磷酸肌醇依赖性蛋白激酶-1（3-phosphoinos
29、itide-dependent protein kinase-1，PDK1PDPK1）是蛋白激酶B（protein kinaseB，PKBCAKT）的上游激酶，通过与3，4，5-三磷酸磷脂酰肌醇Ptdlns（3，4，5）P3作用激活相邻的PKB分子同时，PDK1被称为AGC激酶的掌管者（master），能够激活包含PKB在内的一系列的AGC激酶家族成员PDK1磷酸化这些激酶的保守区域T-loop区，使它们充分激活，从而调节细胞代谢，生长，扩散，生存，抗凋亡等诸多生理过程该文就PDK1调节AGC激酶的活性，与功能上命名的PDK2的关系，PDK1分子自身的调节，PH结构域对自身活性及AGC激酶活性
30、的影响，PDK1定位以及作为一个新药物靶标等方面做了综述蛋白激酶是一类能使蛋白质磷酸化的酶。它能够把腺苷三磷酸（ATP）上的-磷酸转移到蛋白质分子的氨基酸残基上。在大多数情况下，这一磷酸化反应是发生在蛋白质的丝氨酸残基上。蛋白激酶 - 蛋白激酶 一类能使蛋白质磷酸化的酶。它能够把腺苷三磷酸（ATP）上的-磷酸转移到蛋白质分子的氨基酸残基上。在大多数情况下，这一磷酸化反应是发生在蛋白质的丝氨酸残基上。即： 50年代出现的蛋白激酶术语指催化酪蛋白，卵黄高磷蛋白或其他蛋白质磷酸化的酶。70年代在哺乳动物的十多种组织器官中又发现了一类很重要的蛋白激酶环腺苷酸(cAMP)蛋白激酶，以后在昆虫和大肠杆菌中
31、也有报道。 蛋白激酶在细胞内的分布遍及核、线粒体、微粒体和胞液。一般分为3大类。底物专一的蛋白激酶:如磷酸化酶激酶，丙酮酸脱氢酶激酶等。依赖于环核苷酸的蛋白激酶:如环腺苷酸(cAMP)蛋白激酶,环鸟苷酸(cGMP)蛋白激酶。其他蛋白激酶：如组蛋白激酶等。 cAMP蛋白激酶以活化型和非活化型两种形式存在于生物体中，它们的比例受到多种激素的调节控制。cAMP蛋白激酶是由 4个亚基组成两个能与cAMP结合的调节亚基 (R)和两个非活化的能催化磷酸基团转移的催化亚基(C)。如果细胞内 cAMP浓度升高则cAMP蛋白激酶解离成调节双亚基和两个活化的催化亚基（见图）。 蛋白激酶蛋白激酶在供体ATP和活化剂
32、钙离子(吿)存在下,能把低活性的磷酸化酶激酶磷酸化，使它变为高活性的磷酸化酶激酶,后者又能把低活性的磷酸化酶b经磷酸化转变成为高活性的磷酸化酶 a，从而使糖原降解顺利进行。在这同时,蛋白激酶又能使高活性的糖原合成酶a磷酸化成为低活性的糖原合成酶b,使糖原合成速度减慢。这样在cAMP浓度的调节下使糖原的生成和降解代谢达到平衡。 80年代发现了酪氨酸蛋白激酶，它可以催化自身磷酸化，也可以磷酸化其他的蛋白质。其磷酸化反应专一地发生在特定的酪氨酸的羟基上。某些肿瘤病毒的变态蛋白以及一些生长因子的受体具有酪氨酸蛋白激酶活性。AGC蛋白激酶家族的命名取之家族成员蛋白激酶A（PKA）、蛋白激酶G（PKG）和蛋白激酶C（PKC）。在真核细胞中，大部分AGC激酶的效应是通过靶蛋白的丝氨酸或者色氨酸磷酸化所介导的。此蛋白激酶家族成员在大部分已知的受体介导的信号转导通路中发挥重要功能。例如环GMP依赖性激酶（PKG）对血小板激活和血管舒张非常重要，并在MAPK通路、细胞迁移、嗜中性粒细胞失粒、骨发育、凋亡、钙活化、离子通道和基因表达中发挥重要功能。PKC除了能介导跨膜信号转导入胞质这一经典的功能之外，有证据表明，PKC的稳定性对于各种各样的长期细胞应当机制是必须的
