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1 Molecular Nociception Group, Department of Biology, Medawar Building, University College London, Gower Street, London WC1E 6BT, UK
The tetrodotoxin-resistant (TTX-r) persistent Na+ current, attributed to NaV1.9, was recorded in small (< 25 µm apparent diameter) dorsal root ganglion (DRG) neurones cultured from P21 rats and from adult wild-type and NaV1.8 null mice. In conventional whole-cell recordings intracellular GTP-
-S caused current up-regulation, an effect inhibited by the PKC pseudosubstrate inhibitor, PKC19–36. The current amplitude was also up-regulated by 25 µM intracellular 1-oleoyl-2-acetyl-sn-glycerol (OAG) consistent with PKC involvement. In perforated-patch recordings, phorbol 12-myristate 13-acetate (PMA) up-regulated the current, whereas membrane-permeant activators of protein kinase A (PKA) were without effect. PGE2 did not acutely up-regulate the current. Conversely, both PGE2 and PKA activation up-regulated the major TTX-r Na+ current, NaV1.8. Extracellular ATP up-regulated the persistent current with an average apparent Kd near 13 µM, possibly consistent with P2Y receptor activation. Numerical simulation of the up-regulation qualitatively reproduced changes in sensory neurone firing properties. The activation of PKC appears to be a necessary step in the GTP-dependent up-regulation of persistent Na+ current.
(Received 4 May 2005;
accepted after revision 6 July 2005;
first published online 7 July 2005)
Corresponding author M. D. Baker: Molecular Nociception Group, Department of Biology, Medawar Building, University College London, Gower Street, London WC1E 6BT, UK. Email: mark.baker{at}ucl.ac.uk
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