Carbon monoxide is a rapid modulator of recombinant and native P2X(2) ligand-gated ion channels.
OBJECTIVE
Carbon monoxide (CO) is a potent modulator of a wide variety of physiological processes, including sensory signal transduction. Many afferent sensory pathways are dependent upon purinergic neurotransmission, but direct modulation of the P2X purinoceptors by this important, endogenously produced gas has never been investigated.


METHODS
Whole-cell patch-clamp experiments were used to measure ATP-elicited currents in human embryonic kidney 293 cells heterologously expressing P2X(2), P2X(3), P2X(2/3) and P2X(4) receptors and in rat pheochromocytoma (PC12) cells known to express native P2X(2) receptors. Modulation was investigated using solutions containing CO gas and the CO donor molecule, tricarbonyldichlororuthenium (II) dimer (CORM-2).


RESULTS
CO was a potent and selective modulator of native P2X(2) receptors, and these effects were mimicked by a CO donor (CORM-2). Neither pre-incubation with 8-bromoguanosine-3',5'-cyclomonophosphate nor 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (a potent blocker of soluble guanylyl cyclase) affected the ability of the CO donor to enhance the ATP-evoked P2X(2) currents. The CO donor caused a small, but significant inhibition of currents evoked by P2X(2/3) and P2X(4) receptors, but was without effect on P2X(3) receptors.


CONCLUSIONS
These data provided an explanation for how CO might regulate sensory neuronal traffic in physiological reflexes such as systemic oxygen sensing but also showed that CO could be used as a selective pharmacological tool to assess the involvement of homomeric P2X(2) receptors in physiological systems.
Wilkinson
W J
WJ
School of Biosciences, Cardiff University, Cardiff, UK. wilkinsonwj@cf.ac.uk
Gadeberg
H C
HC
Harrison
A W J
AW
Allen
N D
ND
Riccardi
D
D
Kemp
P J
PJ
D000818:Animals; D002248:Carbon Monoxide / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating; D008024:Ligands; D018408:Patch-Clamp Techniques; D055503:Protein Multimerization; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D058848:Receptors, Purinergic P2X4; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors
D008024:Ligands; C546401:P2RX2 protein, human; C546407:P2RX3 protein, human; C548226:P2RX4 protein, human; C546403:P2rx2 protein, rat; C546410:P2rx3 protein, rat; C548228:P2rx4 protein, rat; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D058848:Receptors, Purinergic P2X4; D011994:Recombinant Proteins; D002248:Carbon Monoxide
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