AMP is an adenosine A 1 receptor agonist

Department of Cell and Molecular Physiology, University of North Carolina Neuroscience Center, Chapel Hill, North Carolina 27599, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2012; 287(8):5301-9. DOI: 10.1074/jbc.M111.291666
Source: PubMed


Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related
nucleotide adenosine 5′-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation
in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5′-monophosphonate, ACP) directly activated
the adenosine A1 receptor (A1R). In contrast, AMP only activated the adenosine A2B receptor (A2BR) after hydrolysis to adenosine by ecto-5′-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine
and AMP were equipotent human A1R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons
through activation of endogenous A1R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid and suramin) did not
block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A1R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding
pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically
relevant nucleotide AMP is a full agonist of A1R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases
that hydrolyze this nucleotide to adenosine.

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Available from: Ilia Korboukh, Mar 30, 2015
    • "Benzodiazepines are reported to potentiate the depressant actions of AMP and adenosine on cerebral cortical neurons (Phillis 1979). Studies have demonstrated that AMP and adenosine are equipotent agonists for human A 1 receptors (Rittiner et al. 2012). Hawkins et al. (1988) evaluated, by radioligand, the effects of subcutaneous administration of chronic diazepam (5 mg/kg/day) for 10 and 20 days on adenosine receptors in different brain areas. "
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    • "Other natural product aaRS inhibitors consist of reveromycin A (targets IleRS), borrelidin (targets ThrRS), indolmycin (targets TrpRS), ochratoxin (targets PheRS), cispentacin (targets ProRS), and granaticin (targets LeuRS) [1] [3]. Besides, some synthetic aaRS inhibitors are also developed as variants of the natural substrate or as non-hydrolyzable aa-AMP mimics [4], most of which act through competitive binding to the aaRSs. Although the aa-AMP mimics demonstrated low nanomolar binding affinities against their corresponding aaRSs, the lack of selectivity and poor bacterial cell permeability are the most prominent problems for this new potential class of antibiotics. "
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