The γ2(R43Q) mutation linked to epilepsy affects GABAA receptor internalization
نویسندگان
چکیده
Idiopathic Absence Epilepsies (IAE) are complex syndromes with a strong genetic component. Childhood absence Epilepsy (CAE) is a common form of IAE, affecting children between the age of 3 and 8 years old and that has been associated with mutations in the GABAA receptor. Particularly, a R43Q mutation on the 2 subunit, which impairs GABAA receptor function, has been clearly linked to CAE in animal models and patients. The same mutation has also been linked to febrile seizures, another epileptic syndrome, characterized by a later onset than CAE. GABA is the major inhibitory neurotransmitter in the brain, and dysregulation of GABA synaptic transmission can have drastic effects on neuronal excitability. It is therefore not surprising that mutations impairing the activity of GABAA receptors are involved in epileptic pathologies. This research highlight describes our latest study, dissecting the effect of the R43Q mutation on the receptor’s function.
منابع مشابه
Reduced local input to fast‐spiking interneurons in the somatosensory cortex in the GABAA γ2 R43Q mouse model of absence epilepsy
OBJECTIVE Absence seizures in childhood absence epilepsy are initiated in the thalamocortical (TC) system. We investigated if these seizures result from altered development of the TC system before the appearance of seizures in mice containing a point mutation in γ-aminobutyric acid A (GABAA ) receptor γ2 subunits linked to childhood absence epilepsy (R43Q). Findings from conditional mutant mice...
متن کاملBrief Communication The GABAA Receptor 2 Subunit R43Q Mutation Linked to Childhood Absence Epilepsy and Febrile Seizures Causes Retention of 1 2 2S Receptors in the Endoplasmic Reticulum
The GABAA receptor 2 subunit mutation R43Q is an autosomal dominant mutation associated with childhood absence epilepsy and febrile seizures. Previously, we demonstrated that homozygous 1 3 2L(R43Q) receptor whole-cell currents had reduced amplitude with unaltered time course, suggesting reduced cell surface expression of functional receptors. In human embryonic kidney 293-T cells, we demonstra...
متن کاملLong distance effect on ligand-gated ion channels extracellular domain may affect interactions with the intracellular machinery
Modulation of receptor trafficking is critical for controlling neurotransmission. A γ2(R43Q) point mutation on GABAA receptor subunit is linked to epilepsy in human. We recently analyzed the effect of this amino-acid substitution on GABAA receptor trafficking and showed that this mutation as well as agonist application, both affecting GABAA receptor extracellular domain, have an effect on recep...
متن کاملSAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABAA Receptor γ2 Subunit
The GABAA receptor (GABAAR) α1 subunit A295D epilepsy mutation reduces the surface expression of α1A295Dβ2γ2 GABAARs via ER-associated protein degradation. Suberanilohydroxamic acid (SAHA, also known as Vorinostat) was recently shown to correct the misfolding of α1A295D subunits and thereby enhance the functional surface expression of α1A295Dβ2γ2 GABAARs. Here we investigated whether SAHA can a...
متن کاملIntracortical hyperexcitability in humans with a GABAA receptor mutation.
A missense mutation of the gamma2 subunit of the gamma-aminobutyric acid A (GABA(A)) receptor has been linked to an inherited human generalized epilepsy. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, we tested the hypothesis that the GABRG2(R43Q) mutation alters cortical excitability. Fourteen subjects affected by the GABRG2(R43Q) mutation (5 males, mean...
متن کامل