Aim: 

The slow-channel variant of congenital myasthenic syndromes (SCCMS) is caused by point mutations in the subunits forming the endplate nAChR, which prolong synaptic response and ultimately lead to endplate excitotoxic damage. Research in our laboratories is aimed at exploring the impact of the Ca²⁺permeability of nAChR channel on the pathogenic mechanisms of this disease, as well as at understanding the structural determinants of this functional parameter.

Methods: 

The Ca²⁺ permeability of human endplate nAChRs has been quantified by measuring the fractional Ca²⁺ current (Pf), i.e. the percent of ACh-evoked current transported by Ca²⁺ ions. Measurements were performed on transiently transfected cells, simultaneously recording nicotine-evoked currents and Ca²⁺ transients by patch-clamp and videoimaging techniques, respectively.

Results: 

The human endplate nAChR has a higher Pf than the mouse endplate nAChR, uniquely determined by the human epsilon subunit. The important role of the epsilon subunit was confirmed comparing the effect of the V7'F mutation in the transmembrane M2 segment of the alpha or epsilon subunits. Both mutations cause SCCMS, but only the mutation in the epsilon subunit affects Pf, doubling it in comparison to the wild-type value. However, not all mutations in the epsilon subunit affect the Ca²⁺ permeability of the nAChR.

Conclusion: 

The high Ca²⁺ permeability of the human endplate nAChR is a factor predisposing the human endplate to excitotoxic damage upon hyperstimulation. In some forms of SCCMS, a further contribution derives from the incresed Pf of mutant channels.