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.
Highlights
Gene transcription and thereby induce long term alterations in the biochemistry of sensory neurons
These results indicate that protein kinase C (PKC) stimulation induces an increase of the ASIC3-like current in dorsal root ganglion (DRG) neurons both when the kinase stimulation is direct or when it takes place through G protein-coupled receptors (GPCRs, by serotonin, bradykinin, or DHPG)
As described by Mamet et al [13] in DRG neurons, pH 6.3-evoked ASIC3-like current generates membrane depolarizations that are close to the action potential (AP) threshold
Summary
Gene transcription and thereby induce long term alterations in the biochemistry of sensory neurons. 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.
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