Abstract
Evidence suggesting the involvement of P2X2 and P2X3 in chronic pain has been obtained mostly from rodent models. Here we show that rodents may be poor predictors of P2X3 pharmacology in human. We demonstrate that monkey and human dorsal root ganglion (DRG) neurons do not express appreciable levels of P2X2 subunit, contrary to rat sensory neurons. Additionally, we report functional P2X3 activity in monkey DRG neurons and confirm the absence of functional P2X2/3 receptors. Interestingly, native P2X3 receptors in rat and monkey DRGs show similar agonist potency, but different antagonist potencies for TNP-ATP [2-O-(2,4,6-trinitrophenyl)-ATP] and RO51. This unexpected difference in antagonist potency was confirmed by comparing rat and human P2X3 receptors in HEK293 cells. Mutagenesis studies reveal that two extracellular residues, A197 and T202, are synergistically responsible for the potency drop in primate P2X3 receptors. These results uncover species-specific P2X3 pharmacology and identify key mechanisms impacting the translatability of potential analgesics targeting P2X3 receptors.
MeSH terms
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / pharmacology
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Adult
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Analysis of Variance
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Animals
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Cell Count
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Cells, Cultured
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Child
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Dose-Response Relationship, Drug
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Electric Stimulation
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Female
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Ganglia, Spinal / cytology
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Gene Expression / drug effects
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Gene Expression / physiology*
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Humans
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Macaca fascicularis
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Middle Aged
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Mutagenesis / genetics
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Patch-Clamp Techniques
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Purinergic P2X Receptor Agonists / pharmacology*
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Purinergic P2X Receptor Antagonists / pharmacology*
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Pyrimidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Purinergic P2X / genetics
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Receptors, Purinergic P2X / metabolism*
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Sensory Receptor Cells / drug effects*
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Sensory Receptor Cells / metabolism*
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Species Specificity
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Transfection
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Young Adult
Substances
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Purinergic P2X Receptor Agonists
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Purinergic P2X Receptor Antagonists
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Pyrimidines
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RO-51 compound
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Receptors, Purinergic P2X
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2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate
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Adenosine Triphosphate
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alpha,beta-methyleneadenosine 5'-triphosphate