CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease.
CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease.
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DOI：
10.1016/j.pneurobio.2012.06.001
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发表时间：
2012-10
影响因子：
6.7
通讯作者：
Gould, Todd D.
中科院分区：
文献类型：
--
作者：
Bhat, Shambhu;Dao, David T.;Terrillion, Chantelle E.;Arad, Michal;Smith, Robert J.;Soldatov, Nikolai M.;Gould, Todd D.
关键词：
双相情感障碍基因组全关联研究（GWAS）中最一致的遗传发现之一是与CACNA1C有关，该基因编码Cav1.2电压依赖性l型钙通道（LTCC）的α1C亚基。CACNA1C的遗传变异也与抑郁症、精神分裂症、自闭症谱系障碍以及没有可诊断精神疾病的对照受试者的脑功能和结构变化有关。这些数据与不同诊断和统计手册（DSM）定义的神经精神疾病之间共享的神经生物学脆弱性的连续性一致。虽然参与许多细胞功能，但Cav1.2最常涉及细胞膜去极化与钙膜通透性瞬间增加的耦合，导致细胞内信号通路活性、基因转录和突触可塑性的激活和潜在的变化。Cav1.2参与了许多神经回路的正常功能，包括海马、杏仁核和中边缘奖励系统，这些回路与精神疾病的病理生理密切相关。许多LTCC抑制剂的行为影响已经被描述，包括啮齿动物模型中的抗抑郁样行为作用。临床研究表明，对一部分情绪障碍患者可能有治疗效果。我们回顾了CACNA1C的遗传结构和变异，讨论了相关的人类遗传和临床发现，以及与精神疾病最相关的Cav1.2的生物学作用。
One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the α1C subunit of the Cav1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse—Diagnostic and Statistical Manual (DSM) defined—neuropsychiatric diseases. While involved in numerous cellular functions, Cav1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Cav1.2 is involved in the proper function of numerous neurological circuits including those involving the hippocampus, amygdala, and mesolimbic reward system, which are strongly implicated in psychiatric disease pathophysiology. A number of behavioral effects of LTCC inhibitors have been described including antidepressant-like behavioral actions in rodent models. Clinical studies suggest possible treatment effects in a subset of patients with mood disorders. We review the genetic structure and variation of CACNA1C, discussing relevant human genetic and clinical findings, as well as the biological actions of Cav1.2 that are most relevant to psychiatric illness.
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