An initiator element mediates autologous down-regulation of the human typeA gamma-aminobutyric acid receptor beta 1 subunit gene

The regulated expression of type A gamma-aminobutyric acid receptor (GABA(A )R) subunit genes is postulated to play a role in neuronal maturation, syna ptogenesis, and predisposition to neurological disease. Increases in GABA l evels and changes in GABA(A)R subunit gene expression, including decreased beta 1 mRNA levels, have been observed in animal models of epilepsy. Persis tent exposure to GABA down-regulates GABA(A)R number in primary cultures of neocortical neurons, but the regulatory mechanisms remain unknown. Here, w e report the identification of a TATA-less minimal promoter of 296 bp for t he human GABA(A)R beta 1 subunit gene that is neuron specific and autologou sly down-regulated by GABA. beta 1 promoter activity, mRNA levels, and subu nit protein are decreased by persistent GABA(A)R activation. The core promo ter, 270 bp, contains an initiator element (Inr) at the major transcription al start site. Three concatenated copies of the 10-bp Inr and its immediate 3' flanking sequence produce full neural specific activity that is down-re gulated by GABA in transiently transfected neocortical neurons. Taking thes e results together with those of DNase I footprinting, electrophoretic mobi lity shift analysis, and 2-bp mutagenesis, we conclude that GABA-induced do wn-regulation of beta 1 subunit mRNAs involves the differential binding of a sequence-specific basal transcription factor(s) to the Inr. The results s upport a transcriptional mechanism for the down-regulation of beta 1 subuni t GABA(A)R gene expression and raises the possibility that altered levels o f sequence-specific basal transcription factors may contribute to neurologi cal disorders such as epilepsy.