Structures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments

Xia Yao, Yan Wang, Zhifei Wang, Xiao Fan, Di Wu, Jian Huang, Alexander Mueller, Sarah Gao, Miaohui Hu, Carol V. Robinson, Yong Yu, Shuai Gao () and Nieng Yan ()
Additional contact information
Xia Yao: Princeton University
Yan Wang: St. John’s University
Zhifei Wang: St. John’s University
Xiao Fan: Princeton University
Di Wu: University of Oxford
Jian Huang: Princeton University
Alexander Mueller: Princeton University
Sarah Gao: Princeton University
Miaohui Hu: Princeton University
Carol V. Robinson: University of Oxford
Yong Yu: St. John’s University
Shuai Gao: Princeton University
Nieng Yan: Princeton University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract The R-type voltage-gated Ca2+ (Cav) channels Cav2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson’s disease. Despite their physiological importance, there have lacked selective small-molecule inhibitors targeting these channels. High-resolution structures may aid rational drug design. Here, we report the cryo-EM structure of human Cav2.3 in complex with α2δ−1 and β3 subunits at an overall resolution of 3.1 Å. The structure is nearly identical to that of Cav2.2, with VSDII in the down state and the other three VSDs up. A phosphatidylinositol 4,5-bisphosphate (PIP2) molecule binds to the interface of VSDII and the tightly closed pore domain. We also determined the cryo-EM structure of a Cav2.3 mutant in which a Cav2-unique cytosolic helix in repeat II (designated the CH2II helix) is deleted. This mutant, named ΔCH2, still reserves a down VSDII, but PIP2 is invisible and the juxtamembrane region on the cytosolic side is barely discernible. Our structural and electrophysiological characterizations of the wild type and ΔCH2 Cav2.3 show that the CH2II helix stabilizes the inactivated conformation of the channel by tightening the cytosolic juxtamembrane segments, while CH2II helix is not necessary for locking the down state of VSDII.

Date: 2022
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DOI: 10.1038/s41467-022-35026-6

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