TY - JOUR
T1 - GABA-A Channel Subunit Expression in Human Glioma Correlates with Tumor Histology and Clinical Outcome
AU - Smits, Anja
AU - Jin, Zhe
AU - Elsir, Tamador
AU - Pedder, Hugo
AU - Nistér, Monica
AU - Alafuzoff, Irina
AU - Dimberg, Anna
AU - Edqvist, Per-Henrik
AU - Pontén, Fredrik
AU - Aronica, Eleonora
AU - Birnir, Bryndis
PY - 2012
Y1 - 2012
N2 - GABA (gamma-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 rho 1 and rho 3 subunit were consistently detected. Lowest mRNA levels were found in glioblastoma compared to gliomas of lower malignancy, except for the theta subunit. The expression and cellular distribution of the alpha 1, gamma 1, rho 2 and theta subunit proteins was investigated by immunohistochemistry on tissue microarrays containing 87 gliomas grade II. We found a strong co-expression of rho 2 and theta 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 rho 2 subunit (p = 0.043) but not the theta 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
AB - GABA (gamma-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 rho 1 and rho 3 subunit were consistently detected. Lowest mRNA levels were found in glioblastoma compared to gliomas of lower malignancy, except for the theta subunit. The expression and cellular distribution of the alpha 1, gamma 1, rho 2 and theta subunit proteins was investigated by immunohistochemistry on tissue microarrays containing 87 gliomas grade II. We found a strong co-expression of rho 2 and theta 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 rho 2 subunit (p = 0.043) but not the theta 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
U2 - https://doi.org/10.1371/journal.pone.0037041
DO - https://doi.org/10.1371/journal.pone.0037041
M3 - Article
C2 - 22615883
SN - 1932-6203
VL - 7
SP - e37041
JO - PLOS ONE
JF - PLOS ONE
IS - 5
ER -