Sulfonylurea Receptor Subunit Composition of KATP Channels in Dog and Human Hearts

Abstract

ATP sensitive potassium (KATP) channels are assembled by four pore-forming inward rectifier subunits (Kir6.1 or Kir6.2), each associated with one sulfonylurea subunit (SUR1 or SUR2). The differential subunit composition defines distinct KATP channel properties and tissue-specific function. Although the consensus has been that cardiac KATP channels are SUR2A-based channels, our recent studies indicate that mouse cardiac KATP channels are chamber-specific: SUR1-based channels in atria vs. SUR2A-based channels in ventricles. To test whether chamber specificity is an universal property of cardiac KATP channels in other species, whole-cell and inside-out excised patch-clamp techniques were applied to examine the effects of SUR- specific channel openers (pinacidil acts on SUR2A and diazoxide on SUR1) on isolated dog and human cardiomyocytes. In dog atria, pinacidil- and diazoxide-induced whole-cell currents were 40 ± 4 pA/pF (n = 14) and 13 ± 6 pA/pF (n = 11, p 0.05), respectively; while the ventricular currents were 117 ± 75 pA (n = 3) and 92 (n = 1), respectively. The results indicate that SUR2A-based channels are predominant in dog heart, while abundant SUR1- and SUR2A-based channels co-exist in human heart, in both atria and ventricles. Therefore, there is marked variability between all three species studied, which should be considered carefully when using either mice or dogs to model the effects of human channels in either normal or diseased human hearts.