ERK/MAPK pathway regulates GABAA receptors

A) prevented the UO126-induced enhancement of GABA-gated currents. Collectively, our results implicate the MAPK pathway as a negative modulator of GABAA receptor function, whose influence on GABA-gated currents may be mediated by phosphorylation of the alpha subunit. -->
ISSN: 1097-4695
0022-3034
DOI: 10.1002/neu.20327
Přístupová URL adresa: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0a00f1118dee17e35b46fa1a0cd10370
https://doi.org/10.1002/neu.20327
Rights: CLOSED
Přírůstkové číslo: edsair.doi.dedup.....0a00f1118dee17e35b46fa1a0cd10370
Autor: Quynh Nguyen, Glenn H. Dillon, Meharvan Singh, Cathy L. Bell-Horner, Akiko Dohi
Rok vydání: 2006
Předmět:
Zdroj: Journal of Neurobiology. 66:1467-1474
ISSN: 1097-4695
0022-3034
DOI: 10.1002/neu.20327
Popis: The GABAA receptor is a ligand-gated ion channel whose function and activity can be regulated by ligand binding or alternatively may be influenced indirectly through the phosphorylation of specific subunits that comprise the GABAA receptor pentamer. With respect to phosphorylation, most studies have focused on either beta or gamma subunits, whereas the role of the alpha subunit as a relevant target of signaling kinases is largely unknown. Interestingly, we found a putative phosphorylation site for extracellular-signal regulated kinase (ERK), a key effector of the MAPK pathway, in almost all known alpha subunits of the GABAA receptor, including the ubiquitously expressed alpha1 subunit. To determine whether this putative ERK phosphorylation site was functionally relevant, we evaluated if ERK inhibition (through pharmacological inhibition of its upstream kinase, MEK) altered GABA-gated currents. Using HEK293 cells stably transfected with the alpha1beta2gamma2 form of the GABAA receptor, we found that UO126 reduced basal ERK phosphorylation and resulted in an enhancement of GABA-induced peak current amplitudes. Further, the enhancement of GABA-gated currents required an intact intracellular environment as it was robust in perforated patch recordings (which preserves the intracellular milieu), but absent in conventional whole-cell recordings (which dialyzes the cytosolic contents), supporting the involvement of an intracellular signaling pathway. Finally, mutation of the ERK phosphorylation site (T375-->A) prevented the UO126-induced enhancement of GABA-gated currents. Collectively, our results implicate the MAPK pathway as a negative modulator of GABAA receptor function, whose influence on GABA-gated currents may be mediated by phosphorylation of the alpha subunit.
Databáze: OpenAIRE
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