Altered gamma-aminobutyric acid type B receptor subunit 1 splicing in alcoholics

Changhoon Lee, R. Dayne Mayfield, R. Adron Harris

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Background Chronic alcohol exposure can change splice variant expression. The gamma-aminobutyric acid type B (GABAB) receptor undergoes splicing and is an alcoholism treatment target, but there is little information about splicing changes in this receptor in alcoholics. We studied GABAB receptor subunit 1 (GABAB1) splicing in alcoholic postmortem brains. Methods To maximize GABAB1 splice junction identification, we combined gene specific libraries with RNA-seq. Splice junctions and mapped reads were also found from intronic and intergenic regions. We compared GABAB1 splice junctions in prefrontal cortices from 14 alcoholic and 15 control subjects and introduced new strategies, reads per kilobase of splice junction model per million mapped reads and reads per kilobase of gene model per million mapped reads, for quantitating splice junction and gene expression. Results Novel splice junction detection indicated that the GABAB1 gene is at least two times longer than the previously reported gene length. GABAB1 exon and intron expression data showed low expression at the 5' end exons and exon grouping. This indicated that there are short splicing variants in addition to GABAB receptor subunit GABAB1a, the longest known major transcript. We found that chronic alcohol altered exon/intron expression and splice junction levels. Decreased expression of the gamma-aminobutyric acid binding site, a transmembrane domain and a microRNA binding site may decrease normal GABAB1 transcript population and thereby decrease normal signal transduction in alcoholics. Conclusions We discovered novel, complex splicing of GABAB1 in human brain and showed that chronic alcohol produces additional splicing complexity.

Original languageEnglish (US)
Pages (from-to)765-773
Number of pages9
JournalBiological Psychiatry
Volume75
Issue number10
DOIs
StatePublished - May 15 2014
Externally publishedYes

Keywords

  • Alcoholism
  • exon/intron expression
  • GABAB receptor
  • human prefrontal cortex
  • RNA-Seq
  • splice junction

ASJC Scopus subject areas

  • Biological Psychiatry

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