+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Combining valosin-containing protein (VCP) inhibition and suberanilohydroxamic acid (SAHA) treatment additively enhances the folding, trafficking, and function of epilepsy-associated γ-aminobutyric acid, type A (GABAA) receptors

, : Combining valosin-containing protein (VCP) inhibition and suberanilohydroxamic acid (SAHA) treatment additively enhances the folding, trafficking, and function of epilepsy-associated γ-aminobutyric acid, type A (GABAA) receptors. Journal of Biological Chemistry 290(1): 325-337

GABAA receptors are the primary inhibitory ion channels in the mammalian central nervous system. The A322D mutation in the α1 subunit results in its excessive endoplasmic reticulum-associated degradation at the expense of plasma membrane trafficking, leading to autosomal dominant juvenile myoclonic epilepsy. Presumably, valosin-containing protein (VCP)/p97 extracts misfolded subunits from the endoplasmic reticulum membrane to the cytosolic proteasome for degradation. Here we showed that inhibiting VCP using Eeyarestatin I reduces the endoplasmic reticulum-associated degradation of the α1(A322D) subunit without an apparent effect on its dynamin-1 dependent endocytosis and that this treatment enhances its trafficking. Furthermore, coapplication of Eeyarestatin I and suberanilohydroxamic acid, a known small molecule that promotes chaperone-assisted folding, yields an additive restoration of surface expression of α1(A322D) subunits in HEK293 cells and neuronal SH-SY5Y cells. Consequently, this combination significantly increases GABA-induced chloride currents in whole-cell patch clamping experiments than either chemical compound alone in HEK293 cells. Our findings suggest that VCP inhibition without stress induction, together with folding enhancement, represents a new strategy to restore proteostasis of misfolding-prone GABAA receptors and, therefore, a potential remedy for idiopathic epilepsy.


PMID: 25406314

DOI: 10.1074/jbc.M114.580324

Other references

Burt, M., 1994: Standardized nomenclature of parasitic diseases. The correspondent comments on the letter by R.W. Ashford (Parasitology Today (1994) 10, 143) regarding the standardized nomenclature of parasitic diseases (SNOPAD) and points out that the idea of SNOPAD has been discussed at great length by the co...

Ganry, J., 1976: Search for a correlation between temperature measured under shelter and temperature obtained at the level of growth zones of the banana plant. Fruits 31 (10) 587-598

Richet, C., 1903: De la thalassine, toxine cristallisee pruritogene. C. Biol: 707

Bluhm, H.W.; Hummon, I.F.; Lutterbeck, E.F., 1969: Postoperative treatment of carcinoma of the breast with telecesium. International Surgery 52(4): 290-300

Olson, J.W.; Dent, C.D.; Dominici, J.T.; Lambert, P.M.; Bellome, J.; Bichara, J.; Morris, H.F., 1998: The influence of maxillary sinus augmentation on the success of dental implants through second-stage surgery. An interim evaluation of the status of 102 implants placed in 42 augmented sinuses in 27 patients involved in an alternate category of the Dental Implant Clinical Research Group's long-term, randomized, prospective clinical investigation is p...

Campbell, C.; Barber, J.C.K.; Latif, G.; Sullivan, C.M.; Waters, C.S., 2003: The phenotypic effect of the abnormal cell line in six patients showing mosaicism for a structural chromosome abnormality. Journal of Medical Genetics 40(Supplement 1): S52, September

W.J.ang; Yao BingMing; Jin WenRong, 2005: The biological characteristics of Junli plum cultivar and cultural techniques. Junli is a high quality plum cultivar, widely grown in Zhejiang province. The trees are vigorous, with spreading branches. The flower buds are usually double setting on the fruit branches. This cultivar is self-sterile and its best pollinator is p...

Schjølberg, S.; Eadie, P.; Zachrisson, H.Daae.; Oyen, A-Siri.; Prior, M., 2011: Predicting language development at age 18 months: data from the Norwegian Mother and Child Cohort Study. This study investigated predictors of delayed language development at 18 months of age in a large population cohort of Norwegian toddlers. Data were analyzed on 42,107 toddlers. Language outcome at age 18 months was measured using a standard paren...

Pheasant, J., 1985: Delicious need better pollination. American fruit grower 105(6): 20-21

Ross, W.A.; Caesar, L., 1920: Insects of the Season in Ontario. Injurious insects of 1919, in addition to those already mentioned, include Cydia pomonella (codling moth), which, however, did little damage in well-sprayed orchards; Coleophora fletcherella (cigar case-bearer); Eucosma ocellana (bud moth); Erio-p...