Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2

Summary: N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of...

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Autores principales:	Yanli Dong, Yiwei Gao, Shuai Xu, Yuhang Wang, Zhuoya Yu, Yue Li, Bin Li, Tian Yuan, Bei Yang, Xuejun Cai Zhang, Daohua Jiang, Zhuo Huang, Yan Zhao
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	CaV2.2 closed-state inactivation channel blocker ziconotide N-type voltage-gated calcium channel Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3f815d9bfcb64a66b3a15ec8b32f971b
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spelling	oai:doaj.org-article:3f815d9bfcb64a66b3a15ec8b32f971b2021-11-04T04:29:19ZClosed-state inactivation and pore-blocker modulation mechanisms of human CaV2.22211-124710.1016/j.celrep.2021.109931https://doaj.org/article/3f815d9bfcb64a66b3a15ec8b32f971b2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211124721014042https://doaj.org/toc/2211-1247Summary: N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human CaV2.2 complex in apo, ziconotide-bound, and two CaV2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP2) molecule, which is distinct from the other three VSDs of CaV2.2, as well as activated VSDs observed in previous structures of CaV channels. This structure reveals the molecular basis for the unique inactivation process of CaV2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II–III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.Yanli DongYiwei GaoShuai XuYuhang WangZhuoya YuYue LiBin LiTian YuanBei YangXuejun Cai ZhangDaohua JiangZhuo HuangYan ZhaoElsevierarticleCaV2.2closed-state inactivationchannel blockerziconotideN-typevoltage-gated calcium channelBiology (General)QH301-705.5ENCell Reports, Vol 37, Iss 5, Pp 109931- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CaV2.2 closed-state inactivation channel blocker ziconotide N-type voltage-gated calcium channel Biology (General) QH301-705.5
spellingShingle	CaV2.2 closed-state inactivation channel blocker ziconotide N-type voltage-gated calcium channel Biology (General) QH301-705.5 Yanli Dong Yiwei Gao Shuai Xu Yuhang Wang Zhuoya Yu Yue Li Bin Li Tian Yuan Bei Yang Xuejun Cai Zhang Daohua Jiang Zhuo Huang Yan Zhao Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2
description	Summary: N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human CaV2.2 complex in apo, ziconotide-bound, and two CaV2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP2) molecule, which is distinct from the other three VSDs of CaV2.2, as well as activated VSDs observed in previous structures of CaV channels. This structure reveals the molecular basis for the unique inactivation process of CaV2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II–III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.
format	article
author	Yanli Dong Yiwei Gao Shuai Xu Yuhang Wang Zhuoya Yu Yue Li Bin Li Tian Yuan Bei Yang Xuejun Cai Zhang Daohua Jiang Zhuo Huang Yan Zhao
author_facet	Yanli Dong Yiwei Gao Shuai Xu Yuhang Wang Zhuoya Yu Yue Li Bin Li Tian Yuan Bei Yang Xuejun Cai Zhang Daohua Jiang Zhuo Huang Yan Zhao
author_sort	Yanli Dong
title	Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2
title_short	Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2
title_full	Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2
title_fullStr	Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2
title_full_unstemmed	Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2
title_sort	closed-state inactivation and pore-blocker modulation mechanisms of human cav2.2
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/3f815d9bfcb64a66b3a15ec8b32f971b
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Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2

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