Mutant human β4 subunit identified in amyotrophic lateral sclerosis patients impairs nicotinic receptor function

Recently identified mutations in the genes encoding the neuronal nicotinic ACh receptor (nAChR) subunits in patients affected by sporadic amyotrophic lateral sclerosis (sALS) may represent a factor which enhances disease susceptibility, in particular in association with ambient causes such as cigarette smoking. In this work, we characterize the functional properties of nAChRs containing the β4R349C subunit, the mutation most frequently encountered in sALS patients. The mutation was coexpressed with wild-type α3 or α4 subunits or with mutant α4R487Q subunit, which has been detected in one patient together with β4R349C mutation. None of the functional parameters examined showed differences between α4β4 and α4R487Qβ4 nAChRs. By contrast, β4R349C mutation, independent of the companion α subunit, caused the reduction in potency of both ACh and nicotine, decreased the density of whole-cell current evoked by maximal transmitter concentrations, and altered the kinetics of ACh-evoked whole-cell currents. These data confirm that sALS-associated mutations in nicotinic subunits may markedly perturb cholinergic transmission in individuals bearing the mutations.