Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP

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Abstract
The pharmacological phenotype of ATP-sensitive potassium (K ATP ) channels is defined by their tissue-specific regulatory subunit, the sulfonylurea receptor (SUR), which associates with the pore-forming channel core, Kir6.2. The potassium channel opener diazoxide has hyperglycemic and hypotensive properties that stem from its ability to open K ATP channels in pancreas and smooth muscle. Diazoxide is believed not to have any significant action on cardiac sarcolemmal K ATP channels. Yet, diazoxide can be cardioprotective in ischemia and has been found to bind to the presumed cardiac sarcolemmal K ATP channel-regulatory subunit, SUR2A. Here, in excised patches, diazoxide (300 μM) activated pancreatic SUR1/Kir6.2 currents and had little effect on native or recombinant cardiac SUR2A/Kir6.2 currents. However, in the presence of cytoplasmic ADP (100 μM), SUR2A/Kir6.2 channels became as sensitive to diazoxide as SUR1/Kir6.2 channels. This effect involved specific interactions between MgADP and SUR, as it required Mg 2+ , but not ATP, and was abolished by point mutations in the second nucleotide-binding domain of SUR, which impaired channel activation by MgADP. At the whole-cell level, in cardiomyocytes treated with oligomycin to block mitochondrial function, diazoxide could also activate K ATP currents only after cytosolic ADP had been raised by a creatine kinase inhibitor. Thus, ADP serves as a cofactor to define the responsiveness of cardiac K ATP channels toward diazoxide. The present demonstration of a pharmacological plasticity of K ATP channels identifies a mechanism for the control of channel activity in cardiac cells depending on the cellular ADP levels, which are elevated under ischemia.