Recombinant Mouse PAP Has pH-Dependent Ectonucleotidase Activity and Acts through A1-Adenosine Receptors to Mediate Antinociception
Open Access
- 22 January 2009
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 4 (1), e4248
- https://doi.org/10.1371/journal.pone.0004248
Abstract
Prostatic acid phosphatase (PAP) is expressed in nociceptive neurons and functions as an ectonucleotidase. When injected intraspinally, the secretory isoforms of human and bovine PAP protein have potent and long-lasting antinociceptive effects that are dependent on A1-adenosine receptor (A1R) activation. In this study, we purified the secretory isoform of mouse (m)PAP using the baculovirus expression system to determine if recombinant mPAP also had antinociceptive properties. We found that mPAP dephosphorylated AMP, and to a much lesser extent, ADP at neutral pH (pH 7.0). In contrast, mPAP dephosphorylated all purine nucleotides (AMP, ADP, ATP) at an acidic pH (pH 5.6). The transmembrane isoform of mPAP had similar pH-dependent ectonucleotidase activity. A single intraspinal injection of mPAP protein had long-lasting (three day) antinociceptive properties, including antihyperalgesic and antiallodynic effects in the Complete Freund's Adjuvant (CFA) inflammatory pain model. These antinociceptive effects were transiently blocked by the A1R antagonist 8-cyclopentyl-1, 3-dipropylxanthine (CPX), suggesting mPAP dephosphorylates nucleotides to adenosine to mediate antinociception just like human and bovine PAP. Our studies indicate that PAP has species-conserved antinociceptive effects and has pH-dependent ectonucleotidase activity. The ability to metabolize nucleotides in a pH-dependent manner could be relevant to conditions like inflammation where tissue acidosis and nucleotide release occur. Lastly, our studies demonstrate that recombinant PAP protein can be used to treat chronic pain in animal models.Keywords
This publication has 53 references indexed in Scilit:
- Prostatic Acid Phosphatase Is an Ectonucleotidase and Suppresses Pain by Generating AdenosineNeuron, 2008
- Extracellular pH and Stimulated NeuronsPublished by Wiley ,2007
- Prostatic Acid Phosphatase Is Not a Prostate Specific TargetCancer Research, 2007
- Increased nociceptive response in mice lacking the adenosine A1 receptorPain, 2005
- Cerebrospinal fluid purine metabolite and neuron-specific enolase concentrations after febrile seizuresBrain & Development, 2000
- The Safety and Efficacy of Intrathecal Adenosine in Patients with Chronic Neuropathic PainAnesthesia & Analgesia, 1999
- The Safety and Efficacy of Intrathecal Adenosine in Patients with Chronic Neuropathic PainAnesthesia & Analgesia, 1999
- A proton-gated cation channel involved in acid-sensingNature, 1997
- Interferon-?? in Malignant and Viral DiseasesDrugs, 1993
- A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesiaPain, 1988