GABA-A Channel Subunit Expression in Human Glioma Correlates With Tumor Histology and Clinical Outcome

PLoS One. 2012;7(5):e37041. doi: 10.1371/journal.pone.0037041. Epub 2012 May 17.

Abstract

GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS and is present in high concentrations in presynaptic terminals of neuronal cells. More recently, GABA has been ascribed a more widespread role in the control of cell proliferation during development where low concentrations of extrasynaptic GABA induce a tonic activation of GABA receptors. The GABA-A receptor consists of a ligand-gated chloride channel, formed by five subunits that are selected from 19 different subunit isoforms. The functional and pharmacological properties of the GABA-A channels are dictated by their subunit composition. Here we used qRT-PCR to compare mRNA levels of all 19 GABA-A channel subunits in samples of human glioma (n = 29) and peri-tumoral tissue (n = 5). All subunits except the ρ1 and ρ3 subunit were consistently detected. Lowest mRNA levels were found in glioblastoma compared to gliomas of lower malignancy, except for the θ subunit. The expression and cellular distribution of the α1, γ1, ρ2 and θ subunit proteins was investigated by immunohistochemistry on tissue microarrays containing 87 gliomas grade II. We found a strong co-expression of ρ2 and θ subunits in both astrocytomas (r = 0.86, p<0.0001) and oligodendroglial tumors (r = 0.66, p<0.0001). Kaplan-Meier analysis and Cox proportional hazards modeling to estimate the impact of GABA-A channel subunit expression on survival identified the ρ2 subunit (p = 0.043) but not the θ subunit (p = 0.64) as an independent predictor of improved survival in astrocytomas, together with established prognostic factors. Our data give support for the presence of distinct GABA-A channel subtypes in gliomas and provide the first link between specific composition of the A-channel and patient survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Chloride Channels / genetics
  • Chloride Channels / metabolism
  • Female
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Neoplasm Staging
  • Prognosis
  • Protein Isoforms
  • Protein Subunits
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, GABA / biosynthesis*
  • Receptors, GABA / genetics
  • Retrospective Studies
  • Survival Rate
  • gamma-Aminobutyric Acid / biosynthesis*
  • gamma-Aminobutyric Acid / genetics

Substances

  • Chloride Channels
  • Protein Isoforms
  • Protein Subunits
  • RNA, Messenger
  • Receptors, GABA
  • gamma-Aminobutyric Acid