title: Coupling of cell energetics with membrane metabolic sensing. Integrative signaling through creatine kinase phosphotransfer disrupted by M-CK gene knock-out.
abstract: Transduction of metabolic signals is essential in preserving cellular homeostasis. Yet, principles governing integration and synchronization of membrane metabolic sensors with cell metabolism remain elusive. Here, analysis of cellular nucleotide fluxes and nucleotide-dependent gating of the ATP-sensitive K+ (K(ATP)) channel, a prototypic metabolic sensor, revealed a diffusional barrier within the submembrane space, preventing direct reception of cytosolic signals. Creatine kinase phosphotransfer, captured by 18O-assisted 31P NMR, coordinated tightly with ATP turnover, reflecting the cellular energetic status. The dynamics of high energy phosphoryl transfer through the creatine kinase relay permitted a high fidelity transmission of energetic signals into the submembrane compartment synchronizing K(ATP) channel activity with cell metabolism. Knock-out of the creatine kinase M-CK gene disrupted signal delivery to K(ATP) channels and generated a cellular phenotype with increased electrical vulnerability. Thus, in the compartmentalized cell environment, phosphotransfer systems shunt diffusional barriers and secure regimented signal transduction integrating metabolic sensors with the cellular energetic network.
authors.affiliation: Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology, and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: M Roselle
authors.initials: MR
authors.lastname: Abraham
authors.forename: Vitaliy A
authors.initials: VA
authors.lastname: Selivanov
authors.forename: Denice M
authors.initials: DM
authors.lastname: Hodgson
authors.forename: Darko
authors.initials: D
authors.lastname: Pucar
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Zingman
authors.forename: Be
authors.initials: B
authors.lastname: Wieringa
authors.forename: Petras P
authors.initials: PP
authors.lastname: Dzeja
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Alekseev
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003402:Creatine Kinase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D052283:Creatine Kinase, MM Form; D004734:Energy Metabolism / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000502:physiology
chemical_list: D007527:Isoenzymes; D015221:Potassium Channels; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form