Thursday, September 5, 2013
NMDARs in epilepsy.
Reports by three independent groups suggest mutations in NMDA
receptor NR2A subtype (GRIN2A;
underlie a subset of epilepsy-aphasia spectrum disorders.
groups found de novo mutations in NR2A in 9%-20% of patients
displaying a range of epileptic disorders characterized by abnormal slow wave activity,
seizure and language deficits. Studies in cell culture suggest the
disease-associated mutations lead to abnormal NMDAR kinetics.
childhood, NMDARs are heterotetrameric ion channels (I[a]) consisting of
two subunits of NMDA receptor NR1
and two subunits of NR2A. Normally, binding of the excitatory neurotransmitter glutamate leads to opening of the channel, allowing influx of
ions into neurons (I[b]). After a short time, the channel closes,
leading to moderate accumulation of ions in the cytoplasm and normal
neurological activity (I[c]).
patients with epilepsy-aphasia spectrum disorders, mutations in NR2A (II[a])
compromise the kinetics of NMDAR activity. Glutamate binding to mutant NR2A-containing
NMDARs (II[b]) leads to a prolonged open state (II[c]) and
excessive ion influx, which in turn causes overactivation of downstream
intracellular signaling, speech disorders and seizures.