Selective Reduction of Ca 2+ Entry Through the Human NMDA Receptor: a Quantitative Study by Simultaneous Ca 2+ and Na + Imaging.

Autor: D'Andrea T; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy., Benedetti MC; Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy.; Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy., Monaco L; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy., Rosa A; Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy.; Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy., Fucile S; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. sergio.fucile@uniroma1.it.; IRCCS Neuromed, Pozzilli, IS, Italy. sergio.fucile@uniroma1.it.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2024 Aug; Vol. 61 (8), pp. 5841-5850. Date of Electronic Publication: 2024 Jan 19.
DOI: 10.1007/s12035-024-03944-9
Abstrakt: Excessive Ca 2+ influx through N-methyl-D-aspartate type glutamate receptors (NMDAR) is associated with excitotoxicity and neuronal death, but the inhibition of this receptor-channel causes severe adverse effects. Thus, a selective reduction of NMDA-mediated Ca 2+ entry, leaving unaltered the Na + current, could represent a valid neuroprotective strategy. We developed a new two-fluorophore approach to efficiently assess the Ca 2+ permeability of ligand-gated ion channels, including NMDARs, in different conditions. This technique was able to discriminate differential Ca 2+ /Na + permeation ratio through different receptor channels, and through the same channel in different conditions. With this method, we confirmed that EU1794-4, a negative allosteric modulator of NMDARs, decreased their Ca 2+ permeability. Furthermore, we measured for the first time the fractional Ca 2+ current (P f , i.e. the percentage of the total current carried by Ca 2+ ions) of human NMDARs in the presence of EU1794-4, exhibiting a 40% reduction in comparison to control conditions. EU1794-4 was also able to reduce NMDA-mediated Ca 2+ entry in human neurons derived from induced pluripotent stem cells. This last effect was stronger in the absence of extracellular Mg 2+ , but still significant in its presence, supporting the hypothesis to use NMDA-selective allosteric modulators to lower Ca 2+ influx in human neurons, to prevent Ca 2+ -dependent excitotoxicity and consequent neurodegeneration.
(© 2024. The Author(s).)
Databáze: MEDLINE
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