Reduction of the Ca 2+ permeability of ligand-gated ion channels as a strategy against excitotoxicity

Tiziano D'andrea¹Sergio Fucile^1,2*

• ¹Mediterranean Neurological Institute Neuromed (IRCCS), Pozzilli, Italy
• ²Sapienza University of Rome, Rome, Italy

Excitotoxic damage is due to an excessive Ca 2+ entry in cells following overactivation of Ca 2+ -permeable ion channels. In neurons, Ca 2+ -dependent excitotoxicity is linked to the prominent activation of N-Methyl-d-Aspartate receptors (NMDARs), exhibiting a high permeability to Ca 2+ . Different neurodegenerative diseases share glutamate-and NMDAR-dependent excitotoxicity as a pathogenic mechanism, but also different ligandgated 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 Ca 2+ -permeable LGICs may be counteracted by using molecules able to reduce selectively the Ca 2+ 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 Ca 2+ permeability of LGICs, with a particular focus on the fractional Ca 2+ current (Pf, i.e. the percentage of the total current carried by Ca 2+ ); 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.