期刊
MOLECULAR AND CELLULAR BIOCHEMISTRY
卷 256, 期 1-2, 页码 243-256出版社
SPRINGER
DOI: 10.1023/B:MCBI.0000009872.35940.7d
关键词
ATP-sensitive K(+) channel; nucleotide diffusion; metabolic sensor; intracellular compartment; heart
类别
资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL064822, T32HL007111] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R01 HL064822-05, HL-64822, T32 HL007111, HL-07111, R01 HL064822] Funding Source: Medline
Transmission of energetic signals to membrane sensors, such as the ATP-sensitive K(+) (K(ATP)) channel, is vital for cellular adaptation to stress. Yet, cell compartmentation implies diffusional hindrances that hamper direct reception of cytosolic energetic signals. With high intracellular ATP levels, K(ATP) channels may sense not bulk cytosolic, but rather local submembrane nucleotide concentrations set by membrane ATPases and phosphotransfer enzymes. Here, we analyzed the role of adenylate kinase and creatine kinase phosphotransfer reactions in energetic signal transmission over the strong diffusional barrier in the submembrane compartment, and translation of such signals into a nucleotide response detectable by K(ATP) channels. Facilitated diffusion provided by creatine kinase and adenylate kinase phosphotransfer dissipated nucleotide gradients imposed by membrane ATPases, and shunted diffusional restrictions. Energetic signals, simulated as deviation of bulk ATP from its basal level, were amplified into an augmented nucleotide response in the submembrane space due to failure under stress of creatine kinase to facilitate nucleotide diffusion. Tuning of creatine kinase-dependent amplification of the nucleotide response was provided by adenylate kinase capable of adjusting the ATP/ADP ratio in the submembrane compartment securing adequate K(ATP) channel response in accord with cellular metabolic demand. Thus, complementation between creatine kinase and adenylate kinase systems, here predicted by modeling and further supported experimentally, provides a mechanistic basis for metabolic sensor function governed by alterations in intracellular phosphotransfer fluxes.
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