RT Journal Article
SR Electronic
T1 Pentobarbital Decreases the γ-Aminobutyric AcidAReceptor Subunit gamma-2 Long/Short mRNA Ratio by a Mechanism Distinct from Receptor Occupation
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 350
OP 357
VO 283
IS 1
A1 R. F. Tyndale
A1 S. V. Bhave
A1 E. Hoffmann
A1 P. L. Hoffman
A1 B. Tabakoff
A1 A. J. Tobin
A1 R. W. Olsen
YR 1997
UL http://jpet.aspetjournals.org/content/283/1/350.abstract
AB 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