Ion channel alterations and epilepsy in mice and man

Abstract

Physiological CNS function relies on a balance of impulses mediated by voltage and ligand gated ion channels. Various forms of epilepsy correlate with mutations of genes coding for voltage dependent sodium (e.g., benign familial neonatal seizures), potassium (e.g., benign familial neonatal convulsions), and calcium (e.g., juvenile myoclonic epilepsy) channels. Mice carrying mutations in the orthologous ion channel genes serve as models of corresponding human disorders. From these studies, it has become apparent that ion conducting as well as accessory subunits of these channel types may be affected. The mouse mutant entla develops an absence epilepsy characterized by 2 and 4Hz EEG patterns, in addition to ataxia and paroxysmal dyskinesia. The underlying mutation on mouse Chr 9 was identified as an allele of the Cacna2d2 gene. This gene encodes the accessory α2δ-2 subunit of P/Q type calcium channels, a target of the antiepileptic drug gabapentin. The entla allele harbors an exon duplication that interferes with posttranslational processing, i.e. the formation of a disulfide linkage. This results in a dramatic reduction of both, calcium currents and [3H]gabapentin binding. The entla mouse thus represents a model of genetically alteratered protein processing producing a complex absence epilepsy syndrome. At the postsynaptic face, the neurotransmitter signal is converted to excitatory or inhibitory currents by binding to ligand gated ion channels. Mutations of the nicotinic receptor α4 subunit gene (CHNRA4) cause autosomal dominant nocturnal frontal lobe epilepsy. In contrast, mutations of the glycine subunit genes α1 (GLRA1) and β (GLRB) result in hyperekplexia (startle disease, stiff baby syndrome), a non-epileptic neurological condition. Upon recombinant expression, mutant acetylcholine and glycine receptor subunits frequently display altered transmitter binding and ion conductance.