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

Excitotoxic damage is due to an excessive Ca entry in cells following overactivation of Ca-permeable ion channels. In neurons, Ca-dependent excitotoxicity is linked to the prominent activation of N-Methyl-d-Aspartate receptors (NMDARs), exhibiting a high permeability to Ca. 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 Ca-permeable LGICs may be counteracted by using molecules able to reduce selectively the Ca 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 permeability of LGICs, with a particular focus on the fractional Ca current (P, i.e., the percentage of the total current carried by Ca); (ii) the known Pf values of the main LGICs; (iii) the modulation of the LGIC P values induced by drugs and measured to date. These data support the possibility of fighting excitotoxicity-related pathologies with a new therapeutic approach.