Glycolysis Preferentially Inhibits ATP-Sensitive K ⁺ Channels in Isolated Guinea Pig Cardiac Myocytes

Abstract

In heart, glycolysis may be a preferential source of adenosine triphosphate (ATP) for membrane functions. In this study the patch-clamp technique was used to study potassium channels sensitive to intracellular ATP levels in permeabilized ventricular myocytes. Activation of these K+ channels has been implicated in marked cellular K+ loss leading to electrophysiological abnormalities and arrhythmias during myocardial ischemia. The results showed that glycolysis was more effective than oxidative phosphorylation in preventing ATP-sensitive K+ channels from opening. Experiments in excised inside-out patches suggested that key glycolytic enzymes located in the membrane or adjacent cytoskeleton near the channels may account for their preference for glycolytic ATP.

Nucleotide-gated KATPchannels integrated with creatine and adenylate kinases: Amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment

“…The proposed mechanism, predicted by modeling and supported experimentally, integrates only two major phosphotransfer enzymes, CK and AK, without including other energy converting systems, such as glycolysis, which could modulate the local nucleotide content [29,32]. In fact, active glycolysis would scavenge ADP produced by membrane ATPases maintaining local ATP/ADP ratios and modulating apparent ATPase flux.…”

“…Under severe metabolic challenge, provided that a local regenerating system maintained submembrane ATP levels, AK catalysis could promote the response of the membrane metabolic sensor. Thus, energetic signals generated in the cytosol are processed through CK and AK systems, which provide a mechanistic basis for synchronization of K ATP channel function with cellular metabolism.The proposed mechanism, predicted by modeling and supported experimentally, integrates only two major phosphotransfer enzymes, CK and AK, without including other energy converting systems, such as glycolysis, which could modulate the local nucleotide content [29,32]. In fact, active glycolysis would scavenge ADP produced by membrane ATPases maintaining local ATP/ADP ratios and modulating apparent ATPase flux.…”

“…1C) [25,26], implying that MgADP-dependent K ATP channel regulation is insufficient for channel gating at normally high cytosolic concentrations of ATP (6-10 mM) [27,28]. Rather, K ATP channels could sense local nucleotides set by ATPases in the submembrane space at a level distinct from that of the `bulk' cytosol [25,29,30], provided there exist significant diffusional limitations between the two cellular compartments. Yet, compartmentalization [9,31] would hamper recognition of energetic signals by K ATP channels, as channel gating would be relegated to local fluctuations of nucleotides.…”

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

“…This indicates that the bulk cytosolic nucleotide composition cannot be the sole determinant of K ATP channel function. Rather, K ATP channels could sense local nucleotide concentrations set by ATPases in the submembrane space at a level distinct from that of the "bulk" cytosol [52,54,86], provided that significant diffusional limitations within the cell exist to establish distinct cellular compartments [15,[87][88][89]. However, such cellular compartmentalization would obstruct proper energetic sensing by K ATP channels, as channel gating would be distorted by local fluctuations of nucleotides, remaining weakly dependent on the cellular metabolic status.…”

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

“…41 Besides inhibition of glucose utilization, very high levels of NEFA may alter membrane fluidity because of the accumulation of toxic products in the sarcolemma, sarcoplasmatic reticulum and mitochondrial membranes. 42 The metabolic and molecular alterations induced by Intralipid 1 infusion at the heart level mimic what observed in db=db mice, in which a correlation between several contractility parameters have been studied.…”