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- W4386766638 abstract "The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Small-conductance Ca 2+ -activated K + (K Ca 2 or SK) channels encoded by the KCNN family of genes have emerged from preclinical studies as a key contributor to alcohol-induced functional neuroadaptations in alcohol-drinking monkeys and alcohol dependent mice. Here, this cross-species analysis focused on KCNN3 DNA methylation, gene expression, and single nucleotide polymorphisms including alternative promoters in KCNN3 that could influence surface trafficking and function of K Ca 2 channels. Bisulfite sequencing analysis of the nucleus accumbens tissue from alcohol-drinking monkeys and alcohol dependent mice revealed a differentially methylated region in exon 1A of KCNN3 that overlaps with a predicted promoter sequence. The hypermethylation of KCNN3 in the accumbens paralleled an increase in expression of alternative transcripts that encode apamin-insensitive and dominant-negative K Ca 2 channel isoforms. A polymorphic repeat in macaque KCNN3 encoded by exon 1 did not correlate with alcohol drinking. At the protein level, K Ca 2.3 channel expression in the accumbens was significantly reduced in very heavy drinking monkeys. Together, our cross-species findings on epigenetic dysregulation of KCNN3 represent a complex mechanism that utilizes alternative promoters to impact firing of accumbens neurons. Thus, these results provide support for hypermethylation of KCNN3 as a possible key molecular mechanism underlying harmful alcohol intake and alcohol use disorder." @default.
- W4386766638 created "2023-09-16" @default.
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- W4386766638 date "2023-09-15" @default.
- W4386766638 modified "2023-10-13" @default.
- W4386766638 title "Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking." @default.
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- W4386766638 doi "https://doi.org/10.21203/rs.3.rs-3315122/v1" @default.
- W4386766638 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37790552" @default.
- W4386766638 hasPublicationYear "2023" @default.
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