Structural insights into the GABAA receptor as a target against tumour progression. (#167)
γ –aminobutyric acid (GABA) is well known as the main inhibitory neurotransmitter in the adult central nervous system and acts mainly through the activation of the ligand-gated chloride channel GABAA receptor. However, GABA has another role in addition to that at mature synapses as GABA is the first functional transmitter in the developing brain prior to synapse formation, where it acts as an excitatory transmitter 1 . GABA down-regulates the proliferation of embryonic and adult stem cells of the nervous system and peripheral organs. The involvement of the GABA pathway in the control of cell proliferation and its deregulation in certain cancers makes the GABAA receptor a potential protein target to limit tumour progression 2 . The GABAA receptor is composed of 5 subunits placed symmetrically around a central pore and chosen from at least one of the 19 available subunits: α (1-6), β (1-3), γ (1-3), δ, π, ε, θ and ρ (1-3). The β3 subunit is over represented in proliferating stem cells and precursor cells, with the most common α and γ subunits in neural stem cells being α2 and γ1. We created a homology model of both the GABAA β3 homopentamer and the putative neural stem cell GABAA α2β3γ1 pentamer using the recently solved C.Elegans glutamate-gated chloride channel structure as a template (35% identity) 3. The model was validated with published data and evaluated via molecular dynamics simulations.
- Represa, A. and Y. Ben-Ari, Trophic actions of GABA on neuronal development. Trends Neurosci, 2005. 28(6): p. 278-83.
- Young, S.Z. and A. Bordey, GABA's control of stem and cancer cell proliferation in adult neural and peripheral niches. Physiology (Bethesda), 2009. 24: p. 171-85
- Hibbs, R.E. and E. Gouaux, Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature, 2011. 474(7349): p. 54-60.