ERK/MAPK pathway regulates GABAA receptors

Cathy L. Bell-Horner, Akiko Dohi, Quynh Nguyen, Glenn H. Dillon, Meharvan Singh

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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. β or γ subunits, whereas the role of the α 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 α subunits of the GABAA receptor, including the ubiquitously expressed α1 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 α1β2γ2 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 α subunit.

Original languageEnglish
Pages (from-to)1467-1474
Number of pages8
JournalJournal of Neurobiology
Volume66
Issue number13
DOIs
StatePublished - 1 Nov 2006

Keywords

  • ERK
  • GABA
  • GABA receptor
  • MAPK
  • Phosphorylation

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