Single nucleotide polymorphisms of neuronal CACNA1C L-type calcium channels assoc

描述（由申请人提供）：这是一项新的R21申请，旨在研究神经元钙通道在确定双相情感障碍易感性中的作用。所有可兴奋的细胞都利用其表面的钙离子通道来读取电信号，并将其转化为细胞内钙离子的变化，这是一种无处不在的第二信使。钙控制着大量的细胞过程，包括肌肉收缩、神经递质释放、细胞死亡和神经元生长。钙离子通道是治疗高血压和神经性疼痛的重要药物靶点。CACNA1C钙离子通道基因突变导致一种罕见的遗传性疾病Timothy综合征，最近发现的CACNA1C基因单核苷酸多态性与双相情感障碍有关。双相情感障碍是一种慢性精神疾病，影响了美国近600万成年人，其特征是周期性发作的躁狂和抑郁。最常见的治疗方法是锂，但这种药物只是部分有效，有许多副作用，安全边际很低。双相情感障碍有明显的遗传风险。最近，一项大型的合作全基因组关联研究分析了1万名双相情感障碍患者和对照组，并在人类12号染色体上发现了一个与双相情感障碍有显著关联的区域。双相情感障碍相关的单核苷酸多态性映射到CACNA1C基因一个未表征区域的长内含子。这一激动人心的发现为我们了解CACNA1C基因的单核苷酸变异如何破坏大脑中正常的钙通道活动提供了一个独特的机会。我们将结合基因和RNA分析以及电生理记录来探索CACNA1C双极易感性的潜在位点是如何控制钙离子通道功能的。我们的工作有可能为双相情感障碍的分子机制提供新的见解。)

DESCRIPTION (provided by applicant): This is a new R21 application to study the role of a neuronal calcium channel in determining susceptibility to bipolar disorder. All excitable cells use calcium ion channels on their surface to read electrical signals and convert them into a change in intracellular calcium, a ubiquitous second messenger. Calcium controls a huge number of cellular processes including muscle contraction, neurotransmitter release, cell death and neuronal growth. Calcium ion channels are important drug targets for treating hypertension and neuropathic pain. Mutations in the CACNA1C calcium ion channel gene cause a rare hereditary disorder Timothy Syndrome and single nucleotide polymorphisms identified very recently in the same CACNA1C gene associate with bipolar disorder. Bipolar disorder is a chronic mental illness affecting close to 6 million adults in the United States characterized by cyclical episodes of mania and depression. The most common treatment is lithium but this agent is only partially effective, has numerous side effects, and a low safety margin. There is a clear inheritable risk in bipolar disorder. Recently a large, collaborative genome-wide association study analyzed >10,000 bipolar and control individuals and identified a region in human chromosome 12 that has significant association with bipolar disorder. Bipolar disease-associated single nucleotide polymorphisms mapped to a long intron in an uncharacterized region of the CACNA1C gene. This exciting discovery affords us a unique opportunity to understand how single nucleotide variations in the CACNA1C gene could disrupt normal calcium channel activity in the brain. We will use a combination of gene and RNA analyses, and electrophysiological recordings to explore how this potential site of bipolar susceptibility in CACNA1C controls calcium ion channel function. Our work has the potential to provide novel insights into the molecular mechanisms underlying bipolar disorder. ) PUBLIC HEALTH RELEVANCE: This R21 project will test the hypothesis that a long intron in the CACNA1C gene, recently identified as a risk factor in bipolar disorder, controls calcium channel function through alternative pre-mRNA splicing. We will use a combination of RNA, gene, and electrophysiological analyses to reveal the functional role of intron 4 in controlling L-type calcium channel activity in neurons.