Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP
AUTOR(ES)
D’hahan, Nathalie
FONTE
The National Academy of Sciences
RESUMO
The pharmacological phenotype of ATP-sensitive potassium (KATP) 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 KATP channels in pancreas and smooth muscle. Diazoxide is believed not to have any significant action on cardiac sarcolemmal KATP channels. Yet, diazoxide can be cardioprotective in ischemia and has been found to bind to the presumed cardiac sarcolemmal KATP 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 Mg2+, 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 KATP 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 KATP channels toward diazoxide. The present demonstration of a pharmacological plasticity of KATP channels identifies a mechanism for the control of channel activity in cardiac cells depending on the cellular ADP levels, which are elevated under ischemia.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=18429Documentos Relacionados
- Neuronal selectivity of ATP-sensitive potassium channels in guinea-pig substantia nigra revealed by responses to anoxia.
- Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes.
- Nitric oxide hyperpolarizes rabbit mesenteric arteries via ATP-sensitive potassium channels.
- Modulation of nucleotide sensitivity of ATP-sensitive potassium channels by phosphatidylinositol-4-phosphate 5-kinase
- Multiple blocking mechanisms of ATP-sensitive potassium channels of frog skeletal muscle by tetraethylammonium ions.