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Characterization of the N6-etheno-bridge method to assess extracellular metabolism of adenine nucleotides: detection of a possible role for purine nucleoside phosphorylase in adenosine metabolism

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Abstract

The goal of this study was to determine the validity of using N6-etheno-bridged adenine nucleotides to evaluate ecto-nucleotidase activity. We observed that the metabolism of N6-etheno-ATP versus ATP was quantitatively similar when incubated with recombinant CD39, ENTPD2, ENTPD3, or ENPP-1, and the quantitative metabolism of N6-etheno-AMP versus AMP was similar when incubated with recombinant CD73. This suggests that ecto-nucleotidases process N6-etheno-bridged adenine nucleotides similarly to endogenous adenine nucleotides. Four cell types rapidly (t1/2, 0.21 to 0.66 h) metabolized N6-etheno-ATP. Applied N6-etheno-ATP was recovered in the medium as N6-etheno-ADP, N6-etheno-AMP, N6-etheno-adenosine, and surprisingly N6-etheno-adenine; intracellular N6-etheno compounds were undetectable. This suggests minimal cellular uptake, intracellular metabolism, or deamination of these compounds. N6-etheno-ATP, N6-etheno-ADP, N6-etheno-AMP, N6-etheno-adenosine, and N6-etheno-adenine had little affinity for recombinant A1, A2A, or A2B receptors, for a subset of P2X receptors (3H-α,β-methylene-ATP binding to rat bladder membranes), or for a subset of P2Y receptors (35S-ATP-αS binding to rat brain membranes), suggesting minimal pharmacological activity. N6-etheno-adenosine was partially converted to N6-etheno-adenine in four different cell types; this was blocked by purine nucleoside phosphorylase (PNPase) inhibition. Intravenous N6-etheno-ATP was quickly metabolized, with N6-etheno-adenine being the main product in naïve rats, but not in rats pretreated with a PNPase inhibitor. PNPase inhibition reduced the urinary excretion of endogenous adenine and attenuated the conversion of exogenous adenosine to adenine in the renal cortex. The N6-etheno-bridge method is a valid technique to assess extracellular metabolism of adenine nucleotides by ecto-nucleotidases. Also, rats express an enzyme with PNPase-like activity that metabolizes N6-etheno-adenosine to N6-etheno-adenine.

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Funding

This study was supported by grants from the NIH (NS087978, DK091190, HL109002, HL069846, DK068575, and DK079307).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 100 Technology Drive, Room 514, Pittsburgh, PA, 15219, USA

    Edwin K. Jackson, Delbert G. Gillespie, Dongmei Cheng, Zaichuan Mi & Elizabeth V. Menshikova

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  1. Edwin K. Jackson
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  2. Delbert G. Gillespie
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  3. Dongmei Cheng
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  4. Zaichuan Mi
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  5. Elizabeth V. Menshikova
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Corresponding author

Correspondence to Edwin K. Jackson.

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Conflicts of interest

Edwin K. Jackson declares that he has no conflict of interest.

Delbert G. Gillespie declares that he has no conflict of interest.

Dongmei Cheng declares that he has no conflict of interest.

Zaichuan Mi declares that he has no conflict of interest.

Elizabeth V. Menshikova declares that she has no conflict of interest.

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The Institutional Animal Care and Use Committee approved all procedures.

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Jackson, E.K., Gillespie, D.G., Cheng, D. et al. Characterization of the N6-etheno-bridge method to assess extracellular metabolism of adenine nucleotides: detection of a possible role for purine nucleoside phosphorylase in adenosine metabolism. Purinergic Signalling 16, 187–211 (2020). https://doi.org/10.1007/s11302-020-09699-x

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  • DOI: https://doi.org/10.1007/s11302-020-09699-x

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