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Publication Abstract from PubMed

N-type voltage-gated calcium (Ca(V)) channels mediate Ca(2+) 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 Ca(V)2.2 complex in apo, ziconotide-bound, and two Ca(V)2.2-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 (PIP(2)) molecule, which is distinct from the other three VSDs of Ca(V)2.2, as well as activated VSDs observed in previous structures of Ca(V) channels. This structure reveals the molecular basis for the unique inactivation process of Ca(V)2.2 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.

Closed-state inactivation and pore-blocker modulation mechanisms of human Ca(V)2.2.,Dong Y, Gao Y, Xu S, Wang Y, Yu Z, Li Y, Li B, Yuan T, Yang B, Zhang XC, Jiang D, Huang Z, Zhao Y Cell Rep. 2021 Nov 2;37(5):109931. doi: 10.1016/j.celrep.2021.109931. PMID:34731621^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.