Details

Autor(en) / Beteiligte

• Mulholland, Patrick J
• Padula, Audrey E
• Wilhelm, Larry J
• Park, Byung
• Grant, Kathleen A
• Ferguson, Betsy M
• Cervera-Juanes, Rita

Titel

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking

Ist Teil von

• Translational psychiatry, 2023-11, Vol.13 (1), p.364-364, Article 364

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Nexis

Beschreibungen/Notizen

• The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Small-conductance Ca -activated K (K 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 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 the expression of alternative transcripts that encode apamin-insensitive and dominant-negative K 2 channel isoforms. A polymorphic repeat in macaque KCNN3 encoded by exon 1 did not correlate with alcohol drinking. At the protein level, K 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 potentially impact the 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.