Phosphotransfer reactions in the regulation of ATP-sensitive K⁺ channels

^a Division of Cardiovascular Diseases, Departments of Medicine and Pharmacology, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA

ATP-sensitive K⁺ (K_ATP) channels are nucleotide-gated channels that couple the metabolic status of a cell with membrane excitability and regulate a number of cellular functions, including hormone secretion and cardioprotection. Although intracellular ATP is the endogenous inhibitor of K_ATP channels and ADP serves as the channel activator, it is still a matter of debate whether changes in the intracellular concentrations of ATP, ADP, and/or in the ATP/ADP ratio could account for the transition from the ATP-liganded to the ADP-liganded channel state. Here, we overview evidence for the role of cellular phosphotransfer cascades in the regulation of K_ATP channels. The microenvironment of the K_ATP channel harbors several phosphotransfer enzymes, including adenylate, creatine, and pyruvate kinases, as well as other glycolytic enzymes that are able to transfer phosphoryls between ATP and ADP in the absence of major changes in cytosolic levels of adenine nucleotides. These phosphotransfer reactions are governed by the metabolic status of a cell, and their phosphotransfer rate closely correlates with K_ATP channel activity. Adenylate kinase catalysis accelerates the transition from ATP to ADP, leading to K_ATP channel opening, while phosphotransfers driven by creatine and pyruvate kinases promote ADP to ATP transition and channel closure. Thus, through delivery and removal of adenine nucleotides at the channel site, phosphotransfer reactions could regulate ATP/ADP balance in the immediate vicinity of the channel and thereby the probability of K_ATP channel opening. In this way, phosphotransfer reactions could provide a transduction mechanism coupling cellular metabolic signals with K_ATP channel-associated functions.—Dzeja P. P., Terzic, A. Phosphotransfer reactions in the regulation of ATP-sensitive K⁺ channels. FASEB J. 12, 523–529 (1998)

Key Words: K_ATP channel • adenylate kinase • creatine kinase • pyruvate kinase • glycolysis • metabolic signaling

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