Dataset Information

Regulation of Na(+)/K(+)-ATPase by nuclear respiratory factor 1: implication in the tight coupling of neuronal activity, energy generation, and energy consumption.

ABSTRACT:

Background

NRF-1 regulates mediators of neuronal activity and energy generation.

Results

NRF-1 transcriptionally regulates Na(+)/K(+)-ATPase subunits ?1 and ?1.

Conclusion

NRF-1 functionally regulates mediators of energy consumption in neurons.

Significance

NRF-1 mediates the tight coupling of neuronal activity, energy generation, and energy consumption at the molecular level. Energy generation and energy consumption are tightly coupled to neuronal activity at the cellular level. Na(+)/K(+)-ATPase, a major energy-consuming enzyme, is well expressed in neurons rich in cytochrome c oxidase, an important enzyme of the energy-generating machinery, and glutamatergic receptors that are mediators of neuronal activity. The present study sought to test our hypothesis that the coupling extends to the molecular level, whereby Na(+)/K(+)-ATPase subunits are regulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), found recently by our laboratory to regulate all cytochrome c oxidase subunit genes and some NMDA and AMPA receptor subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutational analysis, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Atp1a1 and Atp1b1 genes but not of the Atp1a3 gene in neurons. The transcripts of Atp1a1 and Atp1b1 subunit genes were up-regulated by KCl and down-regulated by tetrodotoxin. Atp1b1 is positively regulated by NRF-1, and silencing of NRF-1 with small interference RNA blocked the up-regulation of Atp1b1 induced by KCl, whereas overexpression of NRF-1 rescued these transcripts from being suppressed by tetrodotoxin. On the other hand, Atp1a1 is negatively regulated by NRF-1. The binding sites of NRF-1 on Atp1a1 and Atp1b1 are conserved among mice, rats, and humans. Thus, NRF-1 regulates key Na(+)/K(+)-ATPase subunits and plays an important role in mediating the tight coupling between energy consumption, energy generation, and neuronal activity at the molecular level.

SUBMITTER: Johar K

PROVIDER: S-EPMC3504753 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regulation of Na(+)/K(+)-ATPase by nuclear respiratory factor 1: implication in the tight coupling of neuronal activity, energy generation, and energy consumption.

Johar Kaid K Priya Anusha A Wong-Riley Margaret T T MT

The Journal of biological chemistry 20121009 48

<h4>Background</h4>NRF-1 regulates mediators of neuronal activity and energy generation.<h4>Results</h4>NRF-1 transcriptionally regulates Na(+)/K(+)-ATPase subunits α1 and β1.<h4>Conclusion</h4>NRF-1 functionally regulates mediators of energy consumption in neurons.<h4>Significance</h4>NRF-1 mediates the tight coupling of neuronal activity, energy generation, and energy consumption at the molecular level. Energy generation and energy consumption are tightly coupled to neuronal activity at the ce ...[more]

PMID: 23048038

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Project description:The involvement of metabolic energy in platelet responses was investigated by measuring the energy consumption during aggregation and secretion from dense, alpha- and acid-hydrolase-containing granules. Gel-filtered human platelets were stimulated with different amounts of thrombin (0.05-5.0 units X ml-1). At various stages during aggregation and secretion the energy consumption was measured from the changes in metabolic ATP and ADP following abrupt arrest of ATP resynthesis. Stimulation with 5 units of thrombin X ml-1 increased the energy consumption from 6.2 +/- 0.9 to 17.8 +/- 0.4 mumol of ATPeq. X min-1 X (10(11) platelets)-1 during the first 15 s. It decreased thereafter and returned to values found in resting cells after about 30 s. With 0.05 unit of thrombin X ml-1, the energy consumption accelerated more slowly and took at least 3 min before it normalized. A strong positive correlation was found between the velocities of the three secretion responses and the concurrent energy consumption (a) at different stages of the responses induced by a given dose of thrombin, and (b) at different secretion velocities initiated by different amounts of thrombin. When, at different stages of the responses, the extent of secretion was compared with the amount of energy that had been consumed, a strong linear correlation was found with the increment in energy consumption but not with the total energy consumption. This correlation was independent of the concentration of thrombin and indicated that complete secretion from dense, alpha- and acid-hydrolase-containing granules was paralleled by an increment of 4.0, 6.5 and 6.7 mumol of ATPeq. X (10(11) platelets)-1, respectively. An energy cost of 0.7 mumol of ATPeq. X (10(11) platelets)-1 was calculated for separate dense-granule secretion, whereas the combined alpha- and acid-hydrolase granule secretion required 5.3 mumol of ATPeq. X (10(11) platelets)-1. There was no correlation between energy consumption and optical aggregation. In contrast, the rate of single platelet disappearance, which is a measure for the early formation of small aggregates, correlated closely with the rate of energy consumption. Compared with secretion, however, the energy requirement of single platelet disappearance was minor, since 2mM-EDTA completely prevented this response but decreased the energy consumption only slightly. An increase of 0.5-1.0 mumol of ATPeq. X (10(11) platelets)-1 was seen before single platelet disappearance and the three secretion responses were initiated, indicating an increase in energy consuming processes that preceded these responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Dataset Information

Regulation of Na(+)/K(+)-ATPase by nuclear respiratory factor 1: implication in the tight coupling of neuronal activity, energy generation, and energy consumption.

Background

Results

Conclusion

Significance

Publications

Regulation of Na(+)/K(+)-ATPase by nuclear respiratory factor 1: implication in the tight coupling of neuronal activity, energy generation, and energy consumption.

Similar Datasets

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