Related Experiment Video
Updated: Oct 14, 2025

Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time
Published on: March 11, 2021
Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2
Yanli Dong1, Yiwei Gao1, Shuai Xu2
1National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Abstract:
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.
Related Concept Videos
Ligand-Gated Ion Channel Receptor: Gating Mechanism
Mechanically-gated Ion Channels
Non-gated Ion Channels
Compared to the gated ion channels, the non-gated channels, also known as leakage or passive channels, have no gating mechanism....
Voltage-gated Ion Channels
Generally, all voltage-gated ion channels have a 'voltage-sensing domain' that spans the lipid bilayer. The charged residues in the sensor move in response to the membrane potential changes that open the channel allowing ions movement. There are several...
Ligand-gated Ion Channels
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
Depolarizing Blockers: Mechanism of Action
Succinylcholine is the most commonly used depolarizing blocker. Chemically, it constitutes two molecules of acetylcholine joined together by an acetate methyl group. They act on the receptors in the same way as acetylcholine. Because...

