NMDA受容体カルシウム信号に関する通説を覆す発見(UB study overturns prevailing assumptions about NMDA receptor calcium signals)

2025-11-06 バッファロー大学(UB)

This image shows how the environment around synaptic receptors in the brain is constantly changing to reflect the continuous flux of information. Under normal conditions, (center) when the NMDA receptors (the blue and grey wing-shaped bundle at bottom) bind the neurotransmitter glutamate (black dots) that is released by presynaptic terminals (black dots enclosed in white circles), the receptors pass excitatory currents composed of approximately 20% calcium ions. But as the acidity in the environment changes, becoming either not acidic enough (alcalosis, left) or too acidic (acidosis, right) so does the composition of the current that NMDA receptors pass. (Image: Gabriela Popescu)

<関連情報>

• https://www.buffalo.edu/news/releases/2025/11/UB-NMDA-receptor-calcium-current.html
• https://www.pnas.org/doi/abs/10.1073/pnas.2511783122

内因性および合成調節因子によるNMDA受容体Ca2+透過性の動的制御 Dynamic control of NMDA receptor Ca2+ permeability by endogenous and synthetic modulators

Mae G. Weaver and Gabriela K. Popescu
Proceedings of the National Academy of Sciences  Published:October 14, 2025
DOI:https://doi.org/10.1073/pnas.2511783122

Significance

NMDA receptors conduct Ca²⁺-rich excitatory currents, which are essential for learning and memory, and are culprits in severe neuropsychiatric conditions. Drugs acting on the NMDA receptor are presently tested for their ability to control the total current, which assumes that the amount of Ca²⁺ in the fluxed current is constant for a given receptor complex. We demonstrate here that the Ca²⁺ content of the NMDA receptor current varies in real time over a wide range in response to allosteric modulators of endogenous or synthetic origin. These results reveal an unappreciated layer of regulation for processes driven by NMDA receptor Ca²⁺ fluxes and call for preclinical testing of all NMDA receptor–targeted drugs with allosteric mechanisms for their effect on Ca²⁺ permeability.

Abstract

NMDA receptors are principal sources of postsynaptic Ca²⁺ in central neurons. It is widely assumed that the content of Ca²⁺ in the glutamate-elicited ionic flux is determined by the molecular composition of the NMDA receptors, whose expression varies developmentally and across brain regions and can change on a scale of minutes to hours. Here, we report that rather than being a fixed property of a given receptor assembly, the amount of Ca²⁺ in the NMDA receptor current can fluctuate in real time over a wide dynamic range in response to endogenous and synthetic allosteric modulators. We identify the extracellular N-terminal domain of the receptor as a structural modulator of its Ca²⁺ permeability and demonstrate that the mechanism involves changes in the receptor’s unitary Ca²⁺ conductance. These results reveal an unsuspected lever controlling the NMDA receptor–mediated Ca²⁺ transients and, implicitly, the many physiological and pathological processes influenced by these currents.