Role for SUR2A ED Domain in Allosteric Coupling within the KATP Channel Complex

Allosteric regulation of heteromultimeric ATP-sensitive potassium (KATP) channels is unique among protein systems as it implies transmission of ligand-induced structural adaptation at the regulatory SUR subunit, a member of ATP-binding cassette ABCC family, to the distinct pore-forming K+ (Kir6.x) channel module. Cooperative interaction between nucleotide binding domains (NBDs) of SUR is a prerequisite for KATP channel gating, yet pathways of allosteric intersubunit communication remain uncertain. Here, we analyzed the role of the ED domain, a stretch of 15 negatively charged aspartate/glutamate amino acid residues (948–962) of the SUR2A isoform, in the regulation of cardiac KATP channels. Disruption of the ED domain impeded cooperative NBDs interaction and interrupted the regulation of KATP channel complexes by MgADP, potassium channel openers, and sulfonylurea drugs. Thus, the ED domain is a structural component of the allosteric pathway within the KATP channel complex integrating transduction of diverse nucleotide-dependent states in the regulatory SUR subunit to the open/closed states of the K+-conducting channel pore

CARDIOPROTECTION BY PRE- AND POST-CONDITIONING: IMPLICATIONS FOR THE ROLE OF MITOCHONDRIA

The mitochondrion has evolved as an important organelle in determining cell survival and cell death. It is involved in a plethora of processes in mammalian cells including ATP production, steroid synthesis, and cell division and cell death. Indeed, mitochondrial dysfunction is associated with numerous human maladies including heart disease. Mitochondrial diseases have traditionally been attributed to defects in the electron transport chain (ETC), the major source of mitochondrial reactive oxygen species (ROS), a byproduct of mitochondrial respiration. Mitochondrial cation channels and exchangers function to maintain matrix homeostasis and are likely involved in modulating mitochondrial function in part by regulating O2 •- generation. Insofar as mitochondria are involved in oxidative damage that leads to apoptosis, antioxidants and other therapeutic strategies that target the organelle appear to be a novel approach to alleviate some cardiovascular diseases. This novel approach has gained unprecedented attention recently with a significant potential for future therapeutic purpose. Whether mitochondria are targets or end effectors of cardiac pre- and post-conditioning remain unresolved. This brief review will provide the latest information gleaned from the literature on the role of mitochondria in pre- and post-conditioning during cardiac ischemia and reperfusion