Two isoforms of GABAA receptor |[beta]|2 subunit with different electrophysiological properties: differential expression and genotypical correlations in schizophrenia

摘要

Single nucleotide polymorphisms in type A -aminobutyric acid (GABAA) receptor 2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of two alternatively spliced products of GABRB2 along with genotypical disease association analysis. Real-time quantitative polymerase chain reaction, performed with a cohort of 31 schizophrenics and 31 controls of US population, showed 21.7% reduction in the expression of the long isoform 2L, 13.4% in the short isoform 2S and 15.8% in the sum of the two isoforms 2T in postmortem schizophrenic brain. Furthermore, two independent mRNA quantitation methods showed that the relative expression of the long over the short isoforms was significantly decreased, suggesting the occurrence of altered splicing, in schizophrenia. In male schizophrenics, the heterozygous genotypes of rs1876071 (T/C) and rs1876072 (A/G) were correlated with reduced expression of 2L, 2S and 2T, and the heterozygous of rs2546620 (A/G) and homozygous-minor of rs1876071 (C/C) and rs1876072 (G/G) were correlated with reduced expression of 2T. Significant correlations of expression levels with different alleles and haplotypes were also indicated by quantitative trait analysis. Recombinant GABAA receptors expressed in HEK293 human cells containing 2L underwent a steeper current rundown upon repetitive GABA activation than receptors containing 2S. The results thus revealed genotype-dependent expression of the alternatively spliced isoforms of GABAA receptor 2 subunit, giving rise to electrophysiological consequences that could play an important role in the pathogenesis mechanism of schizophrenia.