title: Elimination of allosteric modulation of myocardial KATP channels by ATP and protons in two Kir6.2 polymorphisms found in sudden cardiac death.
abstract: The major cause of sudden cardiac death (SCD) is ventricular arrhythmias due to unstable myocardial electrical activity in which the ATP-sensitive K+ (KATP) channels play a role. Genetic disruption of these channels predisposes the myocardium to arrhythmias. Two point mutations in the Kir6.2 subunit are found in SCD with acute myocardial infarction. Here we show evidence for the functional consequences of the P266T and R371H variants. Baseline single-channel properties, expression density, and channel modulations were studied in patch clamp. We focused on channel modulations by intracellular ATP and protons, as the concentration of these two important KATP channel regulators changes widely with hypoxic ischemia. We found that both variants expressed functional currents even though they occur at two highly conserved regions. The open state probability of P266T was twice as high as the wild-type (WT) channel, whereas its channel density was only approximately 20% of the WT channel. Although the outward current was not affected by these two mutations at neutral pH, it was approximately 20% lower at acidic pH in the P266T than in the WT channel. Both P266T and R371H mutations significantly reduced ATP sensitivity and increased pH sensitivity. More dramatically, allosteric regulation by intracellular ATP and protons was almost completely eliminated in the polymorphic P266T and R371H channels. Such an abnormality was seen in both inward and outward currents. Given the importance and beneficial effects of allosteric regulation in cellular responses to metabolic stress, the loss of such a regulatory mechanism in the P266T and R371H variants appears consistent with the adverse consequences occurring during acute myocardial infarction in patients.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia 30302-4010, USA.
authors.forename: Ningren
authors.initials: N
authors.lastname: Cui
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xueren
authors.initials: X
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shi
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000494:Allosteric Regulation; D002460:Cell Line; D016757:Death, Sudden, Cardiac; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008564:Membrane Potentials; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D017354:Point Mutation; D011110:Polymorphism, Genetic; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011522:Protons; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014162:Transfection; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011522:Protons; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel