@article {Tyndale350, author = {R. F. Tyndale and S. V. Bhave and E. Hoffmann and P. L. Hoffman and B. Tabakoff and A. J. Tobin and R. W. Olsen}, title = {Pentobarbital Decreases the γ-Aminobutyric AcidAReceptor Subunit gamma-2 Long/Short mRNA Ratio by a Mechanism Distinct from Receptor Occupation }, volume = {283}, number = {1}, pages = {350--357}, year = {1997}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Treatment with pentobarbital of primary cultured cerebellar granule cells decreased the γ-aminobutyric acid, (GABA)A receptor subunit gamma-2 long/short (gamma-2L/S) mRNA ratio. A high dose of pentobarbital (500 μM) decreased thegamma-2L/S ratio by 64\%; the decrease was dose and time dependent and reversible. (-)-Hexobarbital (500 μM), the less potent stereoisomer for GABAA receptor activation, decreased the ratio slightly (30\%) but significantly more than (+)-hexobarbital (20\%). Other GABAA receptor activators had no (100 mM ethanol) or little (2 μM 5α-pregnane-3α-ol-20-one) effect on thegamma-2L/S ratio. Furthermore, picrotoxin (10 μM), which blocks the GABA- and pentobarbital-activated GABAAreceptor channel, neither changed the gamma-2L/S ratio nor blocked the pentobarbital-induced changes. These data suggest that barbiturates alter the gamma-2L/S mRNA ratio by a mechanism that does not require GABAA receptor activation. The gamma-2L/S subunit mRNA includes an exon encoding an octapeptide that contains a protein kinase C phosphorylation consensus site. This exon-encoded peptide, occurring in the putative intracellular loop, can be phosphorylated, and in vitro, this phosphorylation has been shown to have functional consequences. This is the first report of a drug-induced alteration in receptor mRNA splicing. Furthermore, the changes in the gamma-2L/S ratio produced by pentobarbital exposure may have significant effects on the function of an important brain protein, the GABAAreceptor. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/283/1/350}, eprint = {https://jpet.aspetjournals.org/content/283/1/350.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }