BIDIRECTIONAL REGULATION OF GABA(A) RECEPTOR ALPHA-1 AND ALPHA-6 SUBUNIT EXPRESSION BY A CYCLIC AMP-MEDIATED SIGNALING MECHANISM IN CEREBELLAR GRANULE CELLS IN PRIMARY CULTURE

Forskolin treatment of cerebellar granule cells in culture resulted in bidirectional regulation of the expression of GABA(A) receptor alpha 1 and alpha 6 subunits. Thus, forskolin applied al 2 days in vitro (DI V) increased expression of the alpha 1 subunit but decreased the expre ssion of the alpha 6 subunit. Values with respect to control cultures, both assayed at 9 DIV by immunoblotting, were 310 +/- 48% for alpha 1 and 25 +/- 16% for the alpha 6 subunit. Similar effects were evoked f ollowing chronic treatment with both dibutyryl cyclic AMP and 3-isobut yl-1-methylxanthine. Dideoxyforskolin had no effect on the level of ex pression of either the al or the alpha 6 GABA(A) receptor subunits. Th e changes in subunit expression were accompanied by a 1.7-fold increas e in number of total specific [H-3]Ro 15-4513 binding sites expressed by intact cerebellar granule cells. This increase in total binding sit es was accommodated by a 2.7-fold increase in number of diazepam-sensi tive Ro 15-4513 binding sites in accordance with the observed increase in alpha 1 subunit expression. The number of diazepam-insensitive sub type of binding sites were not significantly changed. These results su ggest that GABA(A) receptor subtype expression can be differentially r egulated by intracellular cyclic AMP concentration.