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.
Highlights
Gliomas are the most common form of primary brain tumor with an overall incidence of about 4–5 per 100.000 persons per year [1,2]
We studied the distribution of the a1, c1, r2 and h subunit proteins in vivo in a clinical cohort of diffuse low-grade gliomas and correlated the presence of GABA-A channel subunit proteins with patient survival
Statistical analysis of quantitative differences between gliomas grade II, gliomas grade III and glioblastomas showed significantly higher mRNA levels of a1, a6, c1 and c2 GABA-A channel subunits in gliomas grade II compared to glioblastomas, and of a3, a6, b3, c1, c2 and p subunits in gliomas grade III compared to glioblastomas (p,0.05)
Summary
Gliomas are the most common form of primary brain tumor with an overall incidence of about 4–5 per 100.000 persons per year [1,2]. The most common type of GABA receptors is the GABA-A channel, consisting of a ligand-gated pentameric chloride channel that is normally closed but can be opened by GABA [5]. Nineteen different GABA-A channel subunits have been cloned and are grouped into eight separate subfamilies (a1–6, b1–3, c1–3, d, e, h, p and r1–3). All nineteen subunits are expressed in the brain [6]. All neurons contain GABA-A ion channels but the channel subtypes change during development, varying between different brain regions and different types of neurons. The distinctive functional and pharmacological of the GABA-A channels are dictated by the composition of the subunits and can be modulated by intracellular proteins [7]
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