GABA Receptor Regulation by Splicing Truncation

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DESCRIPTION (provided by applicant): The goal is to define the regulatory role of an unusual form of alternative splicing of GABAA receptor alpha4 subunits. GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in the brain. Its type A receptors, GABA-gated chloride channels, are the site of action of drugs used to treat alcohol withdrawal, epilepsy, insomnia, anxiety, etc., and are likely sites of action for alcohol itself. Many subunits (6 alpha, 3 beta, 3 gamma, delta, epsilon, pi, 3 rho, theta) have been cloned in mammals. The alpha4 subunit has been especially implicated in the actions of alcohol. The mRNAs for some subunits exhibit alternative splicing, further increasing subunit diversity. A puzzling form of splicing described for alpha5, alpha6, and rho1 subunits, where it is rare, creates short deletions in the bases coding for the N-terminal extracellular domain which make the resulting subunits nonfunctional. Recently we discovered a relatively common form of alternative splicing of the alpha4 subunit mRNA which, remarkably, creates a message missing everything except the first two coding exons and the last coding exon, with a frameshift between them. This pattern of splicing gives a severely truncated mRNA, not subject to nonsense-mediated mRNA decay, which codes for 2 possible proteins. A short piece of the N-terminus right after the signal peptide is the only one which seems to be made. The splicing is developmentally and regionally regulated. Electrophysiological data suggest that the truncated mRNA, when coexpresssed with the complete alpha4 subunit, selectively reduces currents due to the latter. We plan to explore further whether the truncated alpha4 protein plays a post-translational regulatory role in expression of GABAA receptors containing the alpha4 subunit. These studies may establish a novel and important mechanism of regulation of GABAA receptors responsive to alcohol.