Abraham M Roselle, Selivanov Vitaliy A, Hodgson Denice M, Pucar Darko, Zingman Leonid V, Wieringa Be, Dzeja Petras P, Alekseev Alexey E, Terzic Andre
Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology, and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Biol Chem. 2002 Jul 5;277(27):24427-34. doi: 10.1074/jbc.M201777200. Epub 2002 Apr 19.
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.
代谢信号的转导对于维持细胞内稳态至关重要。然而，关于膜代谢传感器与细胞代谢的整合及同步的原理仍不清楚。在此，对细胞核苷酸通量以及作为典型代谢传感器的ATP敏感性钾通道（K(ATP)通道）的核苷酸依赖性门控进行分析，揭示了亚膜空间内的扩散屏障，阻止了胞质信号的直接接收。通过18O辅助的31P NMR捕获的肌酸激酶磷酸转移与ATP周转紧密协调，反映了细胞的能量状态。通过肌酸激酶中继进行的高能磷酸转移动力学允许将能量信号高保真地传递到亚膜区室，使K(ATP)通道活性与细胞代谢同步。敲除肌酸激酶M-CK基因会破坏信号向K(ATP)通道的传递，并产生电易损性增加的细胞表型。因此，在分隔的细胞环境中，磷酸转移系统绕过扩散屏障，并确保将代谢传感器与细胞能量网络整合的有序信号转导。
