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.