Abstract
Pannexin 1 forms a large membrane channel that, based on its biophysical properties and its expression pattern, is a prime candidate to represent an ATP release channel. Pannexin 1 channel activity is potentially deleterious for cells as indicated by its involvement in the P2X7 death complex. Here we describe a negative feedback loop controlling pannexin 1 channel activity. ATP, permeant to pannexin 1 channels, was found to inhibit its permeation pathway when applied extracellularly to oocytes expressing pannexin 1 exogenously. ATP analogues, including benzoylbenzoyl-ATP, suramin, and brilliant blue G were even more effective inhibitors of pannexin 1 currents than ATP. These compounds also attenuated the uptake of dyes by erythrocytes, which express pannexin 1. The rank order of the compounds in attenuation of pannexin 1 currents was similar to their binding affinities to the P2X7 receptor, except that receptor agonists and antagonists both were inhibitory to the channel. Mutational analysis identified R75 in pannexin 1 to be critical for ATP inhibition of pannexin 1 currents.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / metabolism*
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Adenosine Triphosphate / pharmacology
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Alanine
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Animals
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Binding Sites
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Cell Membrane / drug effects
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Cell Membrane / metabolism*
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Cell Membrane Permeability* / drug effects
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Connexins / antagonists & inhibitors
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Connexins / genetics
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Connexins / metabolism*
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Dose-Response Relationship, Drug
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Erythrocytes / drug effects
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Erythrocytes / metabolism
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Feedback, Physiological
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Membrane Potentials
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Mice
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Mutagenesis, Site-Directed
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Mutation
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Oocytes
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Patch-Clamp Techniques
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Receptors, Purinergic P2 / genetics
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Receptors, Purinergic P2 / metabolism
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Receptors, Purinergic P2X7
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Rosaniline Dyes / pharmacology
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Suramin / pharmacology
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Xenopus
Substances
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Connexins
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Nerve Tissue Proteins
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P2rx7 protein, mouse
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Panx1 protein, mouse
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Receptors, Purinergic P2
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Receptors, Purinergic P2X7
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Rosaniline Dyes
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GJA3 protein, human
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3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
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Suramin
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Adenosine Triphosphate
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coomassie Brilliant Blue
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Alanine