Voltage-Gated Ca2+ Channels. Lessons from Knockout and Knock-in Mice
Voltage-Gated Ca2+ Channels. Lessons from Knockout and Knock-in Mice
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电压门控 Ca2 通道。
DOI：
10.1007/978-3-031-08881-0_11
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Mori Yasuo
中科院分区：
文献类型：
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作者：
Striessnig Jorg;Nakao Akito;Mori Yasuo
电压门控性钙通道的功能多样性是由多个α1亚基编码基因的存在所决定的。为了定义Ca 2+通道类型并了解其生理意义，对药物的敏感性一直是最普遍的标准。然而，并不是所有的类型都具有药理学的优点，因为我们没有针对T-，Q-和某些L-型的选择性高亲和力阻断剂，当它们第一次根据生物物理特性和对L-，N-和P-型选择性阻断剂的抗性进行区分时。此外，α1-亚基基因的数量是成熟类型的两倍，以及辅助亚基对通道的调节，强烈表明应考虑进一步的功能多样性来研究每种Ca 2+通道类型的生理学。为了解决这些问题，基因工程敲除小鼠有助于揭示具有不同α1-亚基的Ca 2+通道不仅发挥特定功能，而且与其他Ca 2+通道在控制生理过程中具有共同作用。具有人类突变的敲入小鼠使我们能够综合了解特定突变如何通过改变Ca 2+通道功能和神经元过程（如传导和突触传递）引起神经表型。在本章中，我们将详细描述现有的Ca 2+通道α1-亚基突变小鼠如何加深我们对Ca 2+通道功能多样性及其个体生理和病理生理功能的理解。
Functional diversification of voltage-gated Ca2+channels is underlain by the existence of multiple α1-subunit-encoding genes. To define Ca2+channel types and to understand their physiological significance, sensitivity to pharmacological agents has been the most prevailing criterion. However, not all the types enjoyed the merit of pharmacology, as we didn’t have selective high-affinity blockers for T-, Q-, and certain L-types, when they were first distinguished on the basis of biophysical properties and resistance to selective blockers of L-, N-, and P-types. Moreover, the number of α1-subunit genes, which doubles that of well-established types, as well as channel modulation by auxiliary subunits, strongly suggested that further functional diversity should be considered to study the physiology of each Ca2+channel type. To address these issues, genetically engineered knockout mice were instrumental to reveal that Ca2+channels with distinct α1-subunits not only play specific functions but also share common roles with other Ca2+channels in controlling physiological processes. Knock-in mice with human mutations have allowed us to integratively understand how specific mutations cause neurological phenotypes by altering Ca2+channel function and neuronal processes such as conduction and synaptic transmission. In this chapter, we will encyclopedically describe how existing Ca2+channel α1-subunit mutant mice have deepened our insights into the functional diversity of Ca2+channels and their individual physiological and pathophysiological functions.