Abstract
ASIC3, an acid-sensing ion channel subunit expressed essentially in sensory neurons, has been proposed to be involved in pain. We show here for the first time that native ASIC3-like currents were increased in cultured dorsal root ganglion (DRG) neurons following protein kinase C (PKC) stimulation. This increase was induced by the phorbol ester PDBu and by pain mediators, such as serotonin, which are known to activate the PKC pathway through their binding to G protein-coupled receptors. We demonstrate that this regulation involves the silent ASIC2b subunit, an ASIC subunit also expressed in sensory neurons. Indeed, heteromultimeric ASIC3/ASIC2b channels, but not homomeric ASIC3 channels, are positively regulated by PKC. The increase of ASIC3/ASIC2b current is accompanied by a shift in its pH dependence toward more physiological pH values and may lead to an increase of sensory neuron excitability. This regulation by PKC requires PICK-1 (protein interacting with C kinase), a PDZ domain-containing protein, which interacts with the ASIC2b C terminus.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Sensing Ion Channels
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Animals
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Blotting, Western
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COS Cells
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Carrier Proteins / metabolism*
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Cell Cycle Proteins
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Cells, Cultured
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Cytoskeletal Proteins
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Degenerin Sodium Channels
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Electrophysiology
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Epithelial Sodium Channels
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Ganglia, Spinal / pathology
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Hydrogen-Ion Concentration
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Ion Channels / metabolism
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Ion Channels / physiology*
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Membrane Proteins / biosynthesis*
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Mice
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Models, Biological
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Models, Genetic
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Mutagenesis
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Mutation
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Nerve Tissue Proteins / biosynthesis*
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Nerve Tissue Proteins / physiology*
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Neurons / metabolism*
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Nuclear Proteins / metabolism*
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Patch-Clamp Techniques
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Phosphorylation
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Plasmids / metabolism
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Protein Kinase C / metabolism
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Protein Structure, Tertiary
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Rats
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Rats, Wistar
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Reverse Transcriptase Polymerase Chain Reaction
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Sodium Channels / biosynthesis*
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Time Factors
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Transfection
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Up-Regulation
Substances
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ASIC3 protein, rat
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Acid Sensing Ion Channels
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Asic2 protein, rat
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Carrier Proteins
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Cell Cycle Proteins
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Cytoskeletal Proteins
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Degenerin Sodium Channels
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Epithelial Sodium Channels
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Ion Channels
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Membrane Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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PICK1 protein, rat
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Prkcabp protein, mouse
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Sodium Channels
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Protein Kinase C