What Determines the Intracellular ATP Concentration

Ataullakhanov, F. I.; Vitvitsky, Victor

doi:10.1023/a:1022069718709

Cited by 133 publications

(101 citation statements)

References 30 publications

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“…1F), indicating that LRP130-mediated increases in ATP require an increase in OXPHOS. Although we did not pursue this further, an increase ATP could entail an imbalance of ATP homeostasis (ATP synthesis that exceeds ATP consumption) or an expansion of the adenylate pool due to increased metabolic demand (46). Even so, our results are consistent with prior reports showing that activation of OXPHOS is sufficient to increase ATP (47,48).…”

Section: Lrp130 Stimulates Oxidative Phosphorylation-lrp130supporting

confidence: 87%

LRP130 Protein Remodels Mitochondria and Stimulates Fatty Acid Oxidation

Liu

Sanosaka

Shi

et al. 2011

Journal of Biological Chemistry

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Background: Impaired oxidative phosphorylation (OXPHOS) is implicated in several metabolic disorders. Hence, molecules that stimulate OXPHOS may prove beneficial. Results: LRP130, a protein involved in Leigh syndrome, activates mitochondrial transcription, which stimulates OXPHOS and oxidative metabolism in cells and mouse liver. Conclusion: By activating mitochondrial transcription, LRP130 remodels mitochondria resulting in denser cristae. Significance: An activator of OXPHOS, LRP130 may mitigate certain metabolic disorders.

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Section: Lrp130 Stimulates Oxidative Phosphorylation-lrp130supporting

confidence: 87%

LRP130 Protein Remodels Mitochondria and Stimulates Fatty Acid Oxidation

Liu

Sanosaka

Shi

et al. 2011

Journal of Biological Chemistry

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“…However, in vivo , intracellular ATP concentrations can vary widely from submillimolar levels up to 10 mM [63–66]. These values vary depending on cell and tissue type [67] and can fluctuate significantly in disease states [68, 69]. Intracellular ATP concentration can also affect cellular function [70–73].…”

Section: Resultsmentioning

confidence: 99%

Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein

Ledwitch

Gibbs

Barnes

et al. 2016

Biochemical Pharmacology

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The P-glycoprotein (Pgp) transporter plays a central role in drug disposition by effluxing a chemically diverse range of drugs from cells through conformational changes and ATP hydrolysis. A number of drugs are known to activate ATP hydrolysis of Pgp, but coupling between ATP and drug binding is not well understood. The cardiovascular drug verapamil is one of the most widely studied Pgp substrates and therefore, represents an ideal drug to investigate the drug-induced ATPase activation of Pgp. As previously noted, verapamil-induced Pgp-mediated ATP hydrolysis kinetics was biphasic at saturating ATP concentrations. However, at subsaturating ATP concentrations, verapamil-induced ATPase activation kinetics became monophasic. To further understand this switch in kinetic behavior, the Pgp-coupled ATPase activity kinetics was checked with a panel of verapamil and ATP concentrations and fit with the substrate inhibition equation and the kinetic fitting software COPASI. The fits suggested that cooperativity between ATP and verapamil switched between low and high verapamil concentration. Fluorescence spectroscopy of Pgp revealed that cooperativity between verapamil and a non-hydrolyzable ATP analog leads to distinct global conformational changes of Pgp. NMR of Pgp reconstituted in liposomes showed that cooperativity between verapamil and the non-hydrolyzable ATP analog modulate each others interactions. This information was used to produce a conformationally-gated model of drug-induced activation of Pgp-mediated ATP hydrolysis.

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“…Hence, intracellular ATP may play an important role in modulating physiological functions of multiple channel families including TRPV channels. The data on fluctuations of nucleotide concentration in cellular physiology are still sparse, but some studies suggest that such variations may be important (37). Thus, changes in cellular nucleotide concentrations reflecting the metabolic state, either local or global, could directly affect TRPV channel sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of TRPV1, TRPV3, and TRPV4 Sensitivity through a Conserved Binding Site on the Ankyrin Repeat Domain

Phelps

Wang

Choo

et al. 2010

Journal of Biological Chemistry

166

181

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Transient receptor potential vanilloid (TRPV) channels, which include the thermosensitive TRPV1-V4, have large cytoplasmic regions flanking the transmembrane domain, including an N-terminal ankyrin repeat domain. We show that a multiligand binding site for ATP and calmodulin previously identified in the TRPV1 ankyrin repeat domain is conserved in TRPV3 and TRPV4, but not TRPV2. Accordingly, TRPV2 is insensitive to intracellular ATP, while, as previously observed with TRPV1, a sensitizing effect of ATP on TRPV4 required an intact binding site. In contrast, ATP reduced TRPV3 sensitivity and potentiation by repeated agonist stimulations. Thus, ATP and calmodulin, acting through this conserved binding site, are key players in generating the different sensitivity and adaptation profiles of TRPV1, TRPV3, and TRPV4. Our results suggest that competing interactions of ATP and calmodulin influence channel sensitivity to fluctuations in calcium concentration and perhaps even metabolic state. Different feedback mechanisms likely arose because of the different physiological stimuli or temperature thresholds of these channels.Transient receptor potential channels, including the six vanilloid (TRPV) 3 channels in warm-blooded vertebrates, have many physiological functions in neuronal and non-neuronal cells (1). TRPV5 and TRPV6 are calcium channels in the gut and kidney important for Ca 2ϩ homeostasis (2), whereas TRPV1-V4 are nonselective cation channels that contribute to temperature sensation (3). TRPV1 and TRPV2 activate at noxious temperatures above 42 and 52°C, respectively, whereas TRPV3 and TRPV4 activate at warm temperatures ϳ33-39 and 25-34°C, respectively.Thermosensitive TRPVs are polymodal channels activated by physical stimuli (e.g. temperature) and chemical agonists. For instance, capsaicin and low extracellular pH activate TRPV1 (4); thymol, carvacrol and eugenol activate TRPV3 (5); and extracellular hypotonicity, phorbol esters, and arachidonic acid metabolites activate TRPV4 (6 -9). 2-Aminoethyl diphenylborinate (2-APB) is promiscuous and activates TRPV1, TRPV2, and TRPV3 (10).Remaining questions include whether TRPV channels have maintained common regulatory mechanisms. Thermosensitive TRPV channels are modulated intracellularly by Ca 2ϩ , calmodulin (CaM), and phosphoinositides (11-13). TRPV1 desensitization depends on intracellular Ca 2ϩ and CaM (14, 15). Similarly, TRPV4 is first potentiated and then inactivated by intracellular Ca 2ϩ , again likely through CaM (16). Like TRPV1, TRPV4 desensitizes after repeated or prolonged stimulations (17). In contrast, TRPV3 currents increase with repeated stimulation (18 -20), and while TRPV3 sensitivity also depends on Ca 2ϩ and CaM, the effects differ from TRPV1 and TRPV4 (21). The nature of these differences in homologous temperaturesensitive TRPVs has yet to be determined.TRPVs have a channel domain homologous to Shaker K ϩ channels and cytosolic N-and C-terminal domains, including a conserved N-terminal ankyrin repeat domain (ARD) (22). TRPV1-, TRPV2-, and TRPV6...

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What Determines the Intracellular ATP Concentration

Cited by 133 publications

References 30 publications

LRP130 Protein Remodels Mitochondria and Stimulates Fatty Acid Oxidation

LRP130 Protein Remodels Mitochondria and Stimulates Fatty Acid Oxidation

Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein

Differential Regulation of TRPV1, TRPV3, and TRPV4 Sensitivity through a Conserved Binding Site on the Ankyrin Repeat Domain

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