Abstract 13506: Evidence for Epigenetic Regulation of Chamber-Specific Structure of Cardiac ATP-Sensitive Potassium (KATP) Channels
KATP channels are widely expressed in the cardiovascular system where they act as key sensors of cell metabolism during metabolic stress. All KATP channels share the same architecture-a K+ channel pore (Kir6.1 or Kir6.2) combines with a sulfonylurea receptor (SUR1, SUR2A or SUR2B) to form a functional channel. We recently discovered that the composition of cardiac sarcolemmal KATP channels is chamber-specific. Atrial KATP is made up of SUR1 and Kir6.2 while ventricular KATP contains SUR2A and Kir6.2. Chamber-specific heterogeneity is driven by differential subunit transcription, with SUR1 subunit mRNA expression greater in mouse atrium compared with ventricle and SUR2 mRNA greater in ventricle than atrium. In order to explore the molecular mechanisms that regulate SUR1 and SUR2 expression in the heart, we employed the HL-1 cell model system. In HL-1 cells, originally derived from atrial myocytes, SUR1 expression is significantly greater than SUR2. We have identified two epigenetic factors that regulate the expression of SURx subunits. First, we observe significant methylation of DNA encompassing distal promoter and first exon of the SUR2 but not SUR1 gene, suggesting that SUR2 expression is selectively suppressed in HL-1 cells by DNA methylation. Second, we found that inhibition of class I and II histone deacetylases with trichostatin A, causes a decrease in SUR1 mRNA with a concomitant increase in SUR2 mRNA. Taken together, these data show that the distribution of SURx transcripts correlates with chamber-specific KATP channel structure. Mechanistically, this distribution of SURx subunits correlates with epigenetic modifications and also suggests that SUR1 and SUR2 expression is coordinated such that only one isoform is dominant in a given cell or tissue at any given time.
- © 2011 by American Heart Association, Inc.