Zanotti S, Mori S, Radaelli R, Perez J, Racagni G, Popoli M
Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Italy.
Neuropharmacology. 1998 Aug;37(8):1081-9. doi: 10.1016/s0028-3908(98)00088-4.
Several lines of evidence suggest that the mechanism of action of antidepressant drugs (AD) involves adaptive changes occurring in intraneuronal post-receptor signal transduction cascades. Protein phosphorylation has a key role in signal transduction and was previously found to be a target in the action of AD (5-HT and/or NA reuptake blockers). Several studies showed that cAMP- and type II Ca2+/calmodulin-dependent protein kinases (PKA and CaMKII) are markedly affected by typical AD in two different and complementary cellular districts, respectively microtubules (a somatodendritic compartment) and synaptic vesicles (a presynaptic terminal compartment). In order to investigate whether the effect on protein kinases may be involved in the therapeutic action of drugs it is interesting to compare the effect of atypical AD with that of typical drugs. In this study the effect of the atypical AD S-adenosylmethionine (SAMe) was tested. Repeated (12 days) SAMe treatment induced in cerebrocortical microtubules an increase in the binding of cAMP to the RII PKA regulatory subunit and an increase in the endogenous phosphorylation of microtubule-associated protein 2, an effect resembling that of typical AD. In synaptic terminals the treatment induced an increase in the activity of CaMKII and in the endogenous phosphorylation of vesicular substrates. However, this modification was found in the cerebral cortex rather than in the hippocampus, where typical AD affect CaMKII. In addition the synapsin I level was decreased in the hippocampus and increased in the cerebral cortex, an effect not detected with typical AD.
多条证据表明，抗抑郁药物（AD）的作用机制涉及神经元内受体后信号转导级联反应中发生的适应性变化。蛋白质磷酸化在信号转导中起关键作用，先前被发现是AD（5-羟色胺和/或去甲肾上腺素再摄取阻滞剂）作用的靶点。多项研究表明，cAMP依赖性蛋白激酶（PKA）和II型Ca2+/钙调蛋白依赖性蛋白激酶（CaMKII）分别在两个不同且互补的细胞区域（即微管，一个体树突状区室；以及突触小泡，一个突触前终末区室）受到典型AD的显著影响。为了研究对蛋白激酶的影响是否可能参与药物的治疗作用，比较非典型AD与典型药物的作用很有意思。在本研究中，测试了非典型AD S-腺苷甲硫氨酸（SAMe）的作用。重复（12天）给予SAMe处理可诱导大脑皮质微管中cAMP与RII PKA调节亚基的结合增加，以及微管相关蛋白2的内源性磷酸化增加，这一效应类似于典型AD的作用。在突触终末，该处理可诱导CaMKII活性增加以及囊泡底物的内源性磷酸化增加。然而，这种改变见于大脑皮质而非海马体，典型AD会影响海马体中的CaMKII。此外，海马体中突触素I水平降低，而大脑皮质中突触素I水平升高，这是典型AD未检测到的效应。
