title: GABA-A channel subunit expression in human glioma correlates with tumor histology and clinical outcome.
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.
authors.affiliation: Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden. anja.smits@neuro.uu.se
authors.forename: Anja
authors.initials: A
authors.lastname: Smits
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.forename: Tamador
authors.initials: T
authors.lastname: Elsir
authors.forename: Hugo
authors.initials: H
authors.lastname: Pedder
authors.forename: Monica
authors.initials: M
authors.lastname: Nistér
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Edqvist
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Bryndis
authors.initials: B
authors.lastname: Birnir
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D020033:Protein Isoforms; D021122:Protein Subunits; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018079:Receptors, GABA / Q000096:biosynthesis* / Q000235:genetics; D012189:Retrospective Studies; D015996:Survival Rate; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018118:Chloride Channels; D020033:Protein Isoforms; D021122:Protein Subunits; D012333:RNA, Messenger; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid