N-type voltage-gated calcium (Ca_V) 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 Ca_V2.2 complex in apo, ziconotide-bound, and two Ca_V2.2-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 Ca_V2.2, 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_V2.2 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.

High-voltage-activated R-type Ca_V2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human Ca_V2.3 in complex with the α2δ1 and β1 subunits. The VSD_II is stabilized in the resting state. Electrophysiological experiments elucidate that the VSD_II is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6_II, which is exclusively conserved in the Ca_V2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5_II helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of Ca_V2 channels.

Through the Cu(I)-catalyzed coupling of diazophosphonates with terminal alkynes, an efficient method for the synthesis of allenylphosphonates has been developed. Simple and inexpensive CuI is used as the catalyst and the reaction is conducted under mild conditions.

Aging-related cognitive decline, including impairments in spatial orientation and memory, has been linked to dysfunction within the hippocampus and medial entorhinal cortex (MEC). However, the cellular and molecular alterations underlying MEC aging remain poorly understood. Here, we show that old mice exhibit a reduced proportion of grid cells and decreased spatial stability. Transcriptomic profiling of the MEC using 10x Genomics Visium technology reveals 1664 differentially expressed genes between young and old mice. Among these, Bglap3 is identified as a marker gene for a subpopulation of layer III neurons that showed an age-associated reduction in cell number. Chemogenetic silencing of Bglap3+ neurons in young mice impairs spatial tuning of MEC neurons. Together, these findings elucidate cellular and molecular mechanisms contributing to age-related MEC dysfunction and suggest that the loss of Bglap3+ neurons may underlie spatial coding deficits in aging.