Mutations linked to autosomal dominant nocturnal frontal lobe epilepsy affect allosteric Ca2+ activation of the alpha 4 beta 2 nicotinic acetylcholine receptor.

Extracellular Ca(2+) robustly potentiates the acetylcholine response of alpha4beta2 nicotinic receptors. Rat orthologs of five mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)-alpha4(S252F), alpha4(S256L), alpha4(+L264), beta2(V262L), and beta2(V262M)-reduced 2 mM Ca(2+) potentiation of the alpha4beta2 1 mM acetylcholine response by 55 to 74%. To determine whether altered allosteric Ca(2+) activation or enhanced Ca(2+) block caused this reduction, we coexpressed the rat ADNFLE mutations with an alpha4 N-terminal mutation, alpha4(E180Q), that abolished alpha4beta2 allosteric Ca(2+) activation.

Five ADNFLE mutations reduce the Ca2+ dependence of the mammalian alpha4beta2 acetylcholine response.

Five nicotinic acetylcholine receptor (nAChR) mutations are currently linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The similarity of their clinical symptoms suggests that a common functional anomaly of the mutations underlies ADNFLE seizures. To identify this anomaly, we constructed rat orthologues (S252F, +L264, S256L, V262L, V262M) of the human ADNFLE mutations, expressed them in Xenopus oocytes with the appropriate wild-type (WT) subunit (alpha4 or beta2), and studied the Ca2+ dependence of their ACh responses.