HDAC Inhibitors Affect Sulfonylurea Receptor Subunit MRNA Expression in Atrial-Derived Hl-1 Cells but not Pancreatic Beta Cell-Derived MIN6 Cells

Abstract

KATP channels are expressed in many types of excitable cells where they typically act as key sensors of cell metabolism. 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. Importantly, KATP channels composition is tissue specific. SUR1 and Kir6.2 make up the channel in atrial cardiomyocytes and pancreatic beta cell, while SUR2A combines with Kir6.2 to form ventricular myocyte KATP. Tissue specific heterogeneity appears to be driven principally by differential subunit transcription, but the mechanisms that determine when and where specific KATP channels are expressed are poorly understood. In this study, we have employed both cardiac- (HL-1) and pancreatic beta cell- (MIN6) derived cell lines to explore the mechanisms that control SURx gene expression. In both HL-1 and MIN6 cells we find that SUR1 expression is significantly greater than SUR2. When cells are treated for 72 hours with trichostatin A (a general inhibitor of histone deacetylases or HDACs), there is a significant increase in SUR2 subunit expression in HL-1 cells, but no apparent change in SUR2 expression in MIN6 cells. This result indicates that in the absence of HDAC activity, the transcriptional machinery to drive SUR2 gene expression is available in HL-1, but not in MIN6 cells. From this data, we conclude that both the SURx subunit transcriptional profile and the mechanisms that determine that profile are tissue specific.