English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

The GABA A  receptor (GABA A R) α1 subunit A295D epilepsy mutation reduces the surface expression of α1 A295D β2γ2 GABA A Rs via ER-associated protein degradation. Suberanilohydroxamic acid (SAHA, also known as Vorinostat) was recently shown to correct the misfolding of α1 A295D  subunits and thereby enhance the functional surface expression of α1 A295D β2γ2 GABA A Rs. Here we investigated whether SAHA can also restore the surface expression of γ2 GABA A R subunits that incorporate epilepsy mutations (N40S, R43Q, P44S, R138G) known to reduce surface expression via ER-associated protein degradation. As a control, we also investigated the γ2  K289M   epilepsy mutation that impairs gating without reducing surface expression. Effects of mutations were evaluated on inhibitory postsynaptic currents (IPSCs) mediated by the major synaptic α1β2γ2 GABA A R isoform. Recordings were performed in neuron-HEK293 cell artificial synapses to minimise contamination by GABA A Rs of undefined subunit composition. Transfection with α1β2γ2  N40S  , α1β2γ2  R43Q  , α1β2γ2  P44S   and α1β2γ2  R138G   subunits produced IPSCs with decay times slower than those of unmutated α1β2γ2 GABA A Rs due to the low expression of mutant γ2 subunits and the correspondingly high expression of slow-decaying α1β2 GABA A Rs. SAHA pre-treatment significantly accelerated the decay time constants of IPSCs consistent with the upregulation of mutant γ2 subunit expression. This increase in surface expression was confirmed by immunohistochemistry. SAHA had no effect on either the IPSC kinetics or surface expression levels of α1β2γ2  K289M   GABA A Rs, confirming its specificity for ER-retained mutant γ2 subunits. We also found that α1β2γ2  K289M   GABA A Rs and SAHA-treated α1β2γ2  R43Q  , α1β2γ2  P44S   and α1β2γ2  R138G   GABA A Rs all mediated IPSCs that decayed at significantly faster rates than wild type receptors as temperature was increased from 22 to 40°C. This may help explain why these mutations cause febrile seizures (FS). Given that SAHA is approved by therapeutic regulatory agencies for human use, we propose that it may be worth investigating as a treatment for epilepsies caused by the N40S, R43Q, P44S and R138G mutations. Although SAHA has already been proposed as a therapeutic for patients harbouring the α1 A295D  epilepsy mutation, the present study extends its potential utility to a new subunit and four new mutations.

SAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABAA Receptor γ2 Subunit