The α1 subunit of GABAA receptor is repressed by c-Myc and is pro-apoptotic

The c-myc oncoprotein plays a critical role in the regulation of cellular proliferation and apoptosis. To mediate these biological functions, a variety of target genes are activated or repressed by c-myc, but few genes have yet been identified that directly mediate c-myc's role in proliferation or apoptosis. During a screen for genes that are repressed by c-myc, we identified the alpha 1 subunit of gamma aminobutyric acid receptor (GABA(A)R-alpha 1) as a novel target of c-myc. GABA(A)R is the major inhibitory neurotransmitter receptor in the mammalian central nervous system and is involved in developmental events in the brain, such as neurite outgrowth, neuronal survival, neuronal migration, and proliferation. We show here that GABA(A)R-alpha 1 expression is rapidly and directly repressed by c-myc. GABA(A)R-alpha 1 expression is elevated in c-myc null cells and upregulation of GABA(A)R-alpha 1 correlates with downregulation of c-myc protein expression during neuronal cell differentiation. We also show that overexpression of GABA(A)R-alpha 1 causes apoptosis, which is blocked by the coexpression of Bcl-2 or Bcl-X-L. Induction of apoptosis is specific for the all subunit, since neither the beta 1 or beta 2 subunits of GABAAR induced apoptosis. Derepression of GABA(A)R-alpha 1 expression upon downregulation of c-myc represents a unique apoptotic mechanism and a distinct function for the alpha 1 subunit, independent of its role as a component of the GABAAR in the plasma membrane. In addition, the regulation of GABA(A)R-alpha 1 expression by c-myc provides a potential direct role for the Myc proteins in neurological processes and neurodegenerative disorders.