Berger Stefan M, Bartsch Dusan
Department of Molecular Biology, Central Institute of Mental Health and Medical Faculty Mannheim, Heidelberg University, 68159, Mannheim, Germany.
Cell Tissue Res. 2014 Aug;357(2):463-76. doi: 10.1007/s00441-014-1936-3. Epub 2014 Jul 5.
The use of specific activators and inhibitors that penetrate the central nervous system has suggested an essential functional role of L-type calcium channels (LTCC) in several important physiological processes of the brain, including the modulation of the mesoaccumbal dopamine signalling pathway, synaptic transmission of auditory stimuli and synaptic plasticity of neutral and aversive learning and memory processes. However, the lack of selectivity of available pharmacological agents towards the most prominent LTCC isoforms in the brain, namely Cav1.2 and Cav1.3, has hampered the elucidation of the precise contribution made by each specific channel isoform within these specific physiological processes. Modern genetic approaches, both in rodents and in human, have recently enhanced our understanding of the selective functional roles of Cav1.2 and Cav1.3 channels. In rodents, the characterisation of global and conditional isoform-specific knockouts suggests a contribution of Cav1.2 channels in spatial memory formation, whereas Cav1.3 channels seem to be involved in the consolidation of fear memories and in neurodegenerative mechanisms associated with the development of Parkinson's disease. With regard to the molecular mechanisms underlying drug addiction, Cav1.3 channels are necessary for the development and Cav1.2 channels for the expression of cocaine and amphetamine behavioural sensitisation. In humans, both the identification of naturally occurring LTCC variants ("channelopathies") and unbiased genome-wide association studies have linked LTCCs to working memory performance in healthy individuals and schizophrenic patients. Individually, CACNA1C polymorphisms and CACNA1D variants have been linked to a variety of psychiatric diseases and to congenital deafness, respectively. However, the contribution of individual LTCCs and their polymorphisms to human brain function and diseases remains unclear, necessitating the use of isoform-specific pharmacological agents.
能够穿透中枢神经系统的特定激活剂和抑制剂的使用表明，L型钙通道（LTCC）在大脑的几个重要生理过程中具有重要的功能作用，包括对中脑伏隔核多巴胺信号通路的调节、听觉刺激的突触传递以及中性和厌恶学习与记忆过程的突触可塑性。然而，现有药理剂对大脑中最突出的LTCC亚型，即Cav1.2和Cav1.3缺乏选择性，这阻碍了我们阐明这些特定生理过程中每个特定通道亚型的确切作用。最近，啮齿动物和人类的现代遗传学方法增进了我们对Cav1.2和Cav1.3通道选择性功能作用的理解。在啮齿动物中，对全局和条件性亚型特异性基因敲除的表征表明，Cav1.2通道在空间记忆形成中起作用，而Cav1.3通道似乎参与恐惧记忆的巩固以及与帕金森病发展相关的神经退行性机制。关于药物成瘾的分子机制，Cav1.3通道对可卡因和苯丙胺行为敏化的发展是必需的，而Cav1.2通道对其表达是必需的。在人类中，天然存在的LTCC变体（“通道病”）的鉴定和无偏全基因组关联研究都将LTCC与健康个体和精神分裂症患者的工作记忆表现联系起来。单独来看，CACNA1C多态性和CACNA1D变体分别与多种精神疾病和先天性耳聋有关。然而，单个LTCC及其多态性对人类脑功能和疾病的贡献仍不清楚，因此需要使用亚型特异性药理剂。
