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J. Biol. Chem. 277 (27): 24427-24434

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Coupling of Cell Energetics with Membrane Metabolic Sensing
INTEGRATIVE SIGNALING THROUGH CREATINE KINASE PHOSPHOTRANSFER DISRUPTED BY M-CK GENE KNOCK-OUT*

M. Roselle Abraham, Vitaliy A. Selivanov, Denice M. Hodgson, Darko Pucar, Leonid V. Zingman, Be WieringaDagger , Petras P. Dzeja, Alexey E. Alekseev, and Andre Terzic§

From the Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology, and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905 and the Dagger  Center for Molecular Life Sciences, University Medical Center, University of Nijmegen, Nijmegen 6500, The Netherlands

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+ (KATP) 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 KATP channel activity with cell metabolism. Knock-out of the creatine kinase M-CK gene disrupted signal delivery to KATP 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.


* This work was supported by National Institutes of Health Grants HL-64822 and HL-07111 and by the American Heart Association, the Guidant Foundation, the Marriott Foundation, the Miami Heart Research Institute, the Bruce and Ruth Rappaport Program in Vascular Biology and Gene Delivery, the American Physicians Fellowship for Medicine in Israel, and the CR Program at the Mayo Clinic.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Established Investigator of the American Heart Association. To whom correspondence should be addressed: Division of Cardiovascular Diseases, Depts. of Medicine, Molecular Pharmacology, and Experimental Therapeutics, Mayo Clinic, Guggenheim 7, 200 First St. SW, Rochester, MN 55905. Tel.: 507-284-2747; Fax: 507-284-9111; E-mail: terzic.andre@mayo.edu.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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