Targeted disruption of the voltage-dependent calcium channel α2/δ-1-subunit
Targeted disruption of the voltage-dependent calcium channel α2/δ-1-subunit
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DOI：
10.1152/ajpheart.00122.2009
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发表时间：
2009-07-01
影响因子：
4.8
通讯作者：
Schwartz, Arnold
中科院分区：
文献类型：
--
作者：
Fuller-Bicer, Geraldine A.;Varadi, Gyula;Schwartz, Arnold
Fuller-Bisher GA、Varadi G、Koch SE、Ishii M、Bodi I、Kadeer N、Muth JN、Mikala G、Petrashevskaya NN、Jordan MA、张S、秦N、Flores CM、Isaacsohn I、Varadi M、Mori Y、Jones WK、Schwartz A.有针对性地干扰电压依赖性钙通道α(2)/增量1亚单位。Am J Physiol心脏圈Physiol 297：H117-H124,2009。2009年5月8日首次出版；DOI：10.1152/ajpheart.00122.2009。-心脏L型电压依赖性钙通道是由α(1)-、α(2)/β-和β-亚基组成的异构体多肽复合体。α2/Delta-1亚基对加巴喷丁具有立体选择性、高亲和力的结合部位，广泛用于治疗癫痫和带状疱疹后神经痛以及睡眠障碍。电压依赖性钙通道的α(2)/Delta亚基突变与包括癫痫在内的不同疾病有关。多种异源共表达系统已经被用于研究α(2)/β-1亚基缺失的影响，但试图建立传统的基因敲除动物模型是无效的。我们报道了使用针对α(2)/Delta-1的第二外显子的构建，开发了一种可存活的常规基因敲除小鼠。虽然该亚单位的缺失不是致命性的，但这些动物缺乏高亲和力的加巴喷丁结合部位，表现出基础心肌收缩和舒张性显著降低，L型钙电流峰值幅度降低。这是一个研究α(2)/β-1亚基功能的新模型，将对开发新的药物治疗方法具有重要意义。
Fuller-Bicer GA, Varadi G, Koch SE, Ishii M, Bodi I, Kadeer N, Muth JN, Mikala G, Petrashevskaya NN, Jordan MA, Zhang S, Qin N, Flores CM, Isaacsohn I, Varadi M, Mori Y, Jones WK, Schwartz A. Targeted disruption of the voltage-dependent calcium channel alpha(2)/delta 1-subunit. Am J Physiol Heart Circ Physiol 297: H117-H124, 2009. First published May 8, 2009; doi:10.1152/ajpheart.00122.2009.-Cardiac L-type voltage-dependent Ca2+ channels are heteromultimeric polypeptide complexes of alpha(1)-, alpha(2)/delta-, and beta-subunits. The alpha 2/delta-1-subunit possesses a stereoselective, high-affinity binding site for gabapentin, widely used to treat epilepsy and postherpetic neuralgic pain as well as sleep disorders. Mutations in alpha(2)/delta-subunits of voltage- dependent Ca2+ channels have been associated with different diseases, including epilepsy. Multiple heterologous coexpression systems have been used to study the effects of the deletion of the alpha(2)/delta-1-subunit, but attempts at a conventional knockout animal model have been ineffective. We report the development of a viable conventional knockout mouse using a construct targeting exon 2 of alpha(2)/delta-1. While the deletion of the subunit is not lethal, these animals lack high-affinity gabapentin binding sites and demonstrate a significantly decreased basal myocardial contractility and relaxation and a decreased L-type Ca2+ current peak current amplitude. This is a novel model for studying the function of the alpha(2)/delta-1-subunit and will be of importance in the development of new pharmacological therapies.