Abstract
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 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(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 (P(f), 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 P(f) values induced by drugs and measured to date. These data support the possibility of fighting excitotoxicity-related pathologies with a new therapeutic approach.