Altered GABAA receptor expression and seizure threshold following acute ethanol challenge in mice lacking the RIIβ subunit of PKA

Neurochem Res. 2014 Jun;39(6):1079-87. doi: 10.1007/s11064-013-1167-0. Epub 2013 Oct 9.

Abstract

Ethanol causes pathological changes in GABAA receptor trafficking and function. These changes are mediated in part by ethanol activation of protein kinase A (PKA). The current study investigated the expression of the GABAA α1 and α4 subunits and the kinase anchoring protein AKAP150, as well as bicuculline-induced seizure threshold, at baseline and following acute injection of ethanol (3.5 g/kg IP) in a mouse line lacking the regulatory RIIβ subunit of PKA. Whole cerebral cortices were harvested at baseline, 1 h, or 46 h following injection of ethanol or saline and subjected to fractionation and western blot analysis. Knockout (RIIβ-/-) mice had similar baseline levels of PKA RIIα and GABAA α1 and α4 subunits compared to wild type (RIIβ+/+) littermates, but had deficits in AKAP150. GABAA α1 subunit levels were decreased in the P2 fraction of RIIβ-/-, but not RIIβ+/+, mice following 1 h ethanol, an effect that was driven by decreased α1 expression in the synaptic fraction. GABAA α4 subunits in the P2 fraction were not affected by 1 h ethanol; however, synaptic α4 subunit expression was increased in RIIβ+/+, but not RIIβ-/- mice, while extrasynaptic α4 and δ subunit expression were decreased in RIIβ-/-, but not RIIβ+/+ mice. Finally, RIIβ knockout was protective against bicuculline-induced seizure susceptibility. Overall, the results suggest that PKA has differential roles in regulating GABAA receptor subunits. PKA may protect against ethanol-induced deficits in synaptic α1 and extrasynaptic α4 receptors, but may facilitate the increase of synaptic α4 receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit / deficiency*
  • Ethanol / administration & dosage*
  • Gene Expression Regulation*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, GABA-A / biosynthesis*
  • Seizures / chemically induced
  • Seizures / metabolism*

Substances

  • Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit
  • Receptors, GABA-A
  • Ethanol