Inflammatory mediators potentiate ATP-gated channels through the P2X(3) subunit.
The P2X(3) receptor is an ATP-gated ion channel predominantly expressed in nociceptive neurons from the dorsal root ganglion. P2X(3) receptor channels are highly expressed in sensory neurons and probably contribute to the sensation of pain. Kinetics of P2X(3) currents are characterized by rapid desensitization (<100 ms) and slow recovery (>20 s). Thus, any mechanism modulating rate of desensitization and/or recovery may have profound effect on susceptibility of nociceptive neurons expressing P2X(3) to ATP. Here we show that currents mediated by P2X(3) receptor channels and the heteromeric channel P2X(2/3) composed of P2X(2) and P2X(3) subunits are potentiated by the neuropeptides substance P and bradykinin, which are known to modulate pain perception. The effect is mediated by the respective neuropeptide receptors, can be mimicked by phorbol ester and blocked by inhibitors of protein kinases. Together with data from site-directed mutagenesis our results suggest that inflammatory mediators sensitize nociceptors through phosphorylation of P2X(3) and P2X(2/3) ion channels or associated proteins.
Paukert
M
M
Department of Otolaryngology, Division of Sensory Biophysics, Röntgenweg 11, D-72076 Tübingen, Germany.
Osteroth
R
R
Geisler
H S
HS
Brandle
U
U
Glowatzki
E
E
Ruppersberg
J P
JP
Gründer
S
S
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000502:physiology; D009479:Neuropeptides / Q000502:physiology; D009619:Nociceptors / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D011487:Protein Conformation; D021122:Protein Subunits; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014982:Xenopus laevis
D002712:Chlorides; D009479:Neuropeptides; D021122:Protein Subunits; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D011993:Recombinant Fusion Proteins; D013373:Substance P; D000255:Adenosine Triphosphate; D013755:Tetradecanoylphorbol Acetate; D001920:Bradykinin