Reduction of the Ca2+ permeability of ligand-gated ion channels as a strategy against excitotoxicity
Excitotoxic damage is due to an excessive Ca2+ entry in cells following overactivation of Ca2+-permeable ion channels. In neurons, Ca2+-dependent excitotoxicity is linked to the prominent activation of N-Methyl-d-Aspartate receptors (NMDARs), exhibiting a high permeability to Ca2+. Different neurode...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2025.1617006/full |
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| author | Tiziano D’Andrea Sergio Fucile Sergio Fucile |
| author_facet | Tiziano D’Andrea Sergio Fucile Sergio Fucile |
| author_sort | Tiziano D’Andrea |
| collection | DOAJ |
| description | Excitotoxic damage is due to an excessive Ca2+ entry in cells following overactivation of Ca2+-permeable ion channels. In neurons, Ca2+-dependent excitotoxicity is linked to the prominent activation of N-Methyl-d-Aspartate receptors (NMDARs), exhibiting a high permeability to Ca2+. Different neurodegenerative diseases share glutamate-and NMDAR-dependent excitotoxicity as a pathogenic mechanism, but also different ligand-gated ion channels (LGICs) may be involved in excitotoxic-related pathologies, such as muscle nicotinic acetylcholine receptor in some forms of congenital myasthenic syndrome. We posit that excitotoxicity due to the overactivation of Ca2+-permeable LGICs may be counteracted by using molecules able to reduce selectively the Ca2+ entry, without blocking Na+ influx, thus reducing the adverse effects induced by channel blockers. In this review, we recapitulate: (i) the techniques used to quantify the Ca2+ permeability of LGICs, with a particular focus on the fractional Ca2+ current (Pf, i.e., the percentage of the total current carried by Ca2+); (ii) the known Pf values of the main LGICs; (iii) the modulation of the LGIC Pf values induced by drugs and measured to date. These data support the possibility of fighting excitotoxicity-related pathologies with a new therapeutic approach. |
| format | Article |
| id | doaj-art-6fbd418a3afd498abeac869901ac65c9 |
| institution | Kabale University |
| issn | 1662-5102 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj-art-6fbd418a3afd498abeac869901ac65c92025-08-20T03:30:24ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022025-07-011910.3389/fncel.2025.16170061617006Reduction of the Ca2+ permeability of ligand-gated ion channels as a strategy against excitotoxicityTiziano D’Andrea0Sergio Fucile1Sergio Fucile2IRCCS Neuromed, Pozzilli, ItalyIRCCS Neuromed, Pozzilli, ItalyDepartment of Physiology and Pharmacology, Sapienza Rome University, Rome, ItalyExcitotoxic damage is due to an excessive Ca2+ entry in cells following overactivation of Ca2+-permeable ion channels. In neurons, Ca2+-dependent excitotoxicity is linked to the prominent activation of N-Methyl-d-Aspartate receptors (NMDARs), exhibiting a high permeability to Ca2+. Different neurodegenerative diseases share glutamate-and NMDAR-dependent excitotoxicity as a pathogenic mechanism, but also different ligand-gated ion channels (LGICs) may be involved in excitotoxic-related pathologies, such as muscle nicotinic acetylcholine receptor in some forms of congenital myasthenic syndrome. We posit that excitotoxicity due to the overactivation of Ca2+-permeable LGICs may be counteracted by using molecules able to reduce selectively the Ca2+ entry, without blocking Na+ influx, thus reducing the adverse effects induced by channel blockers. In this review, we recapitulate: (i) the techniques used to quantify the Ca2+ permeability of LGICs, with a particular focus on the fractional Ca2+ current (Pf, i.e., the percentage of the total current carried by Ca2+); (ii) the known Pf values of the main LGICs; (iii) the modulation of the LGIC Pf values induced by drugs and measured to date. These data support the possibility of fighting excitotoxicity-related pathologies with a new therapeutic approach.https://www.frontiersin.org/articles/10.3389/fncel.2025.1617006/fullneuroprotectionneurodegenerationNMDA receptornicotinic acetylcholine receptorfractional Ca2+ current |
| spellingShingle | Tiziano D’Andrea Sergio Fucile Sergio Fucile Reduction of the Ca2+ permeability of ligand-gated ion channels as a strategy against excitotoxicity Frontiers in Cellular Neuroscience neuroprotection neurodegeneration NMDA receptor nicotinic acetylcholine receptor fractional Ca2+ current |
| title | Reduction of the Ca2+ permeability of ligand-gated ion channels as a strategy against excitotoxicity |
| title_full | Reduction of the Ca2+ permeability of ligand-gated ion channels as a strategy against excitotoxicity |
| title_fullStr | Reduction of the Ca2+ permeability of ligand-gated ion channels as a strategy against excitotoxicity |
| title_full_unstemmed | Reduction of the Ca2+ permeability of ligand-gated ion channels as a strategy against excitotoxicity |
| title_short | Reduction of the Ca2+ permeability of ligand-gated ion channels as a strategy against excitotoxicity |
| title_sort | reduction of the ca2 permeability of ligand gated ion channels as a strategy against excitotoxicity |
| topic | neuroprotection neurodegeneration NMDA receptor nicotinic acetylcholine receptor fractional Ca2+ current |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2025.1617006/full |
| work_keys_str_mv | AT tizianodandrea reductionoftheca2permeabilityofligandgatedionchannelsasastrategyagainstexcitotoxicity AT sergiofucile reductionoftheca2permeabilityofligandgatedionchannelsasastrategyagainstexcitotoxicity AT sergiofucile reductionoftheca2permeabilityofligandgatedionchannelsasastrategyagainstexcitotoxicity |