Protein kinase C mediates up‐regulation of tetrodotoxin‐resistant, persistent Na + current in rat and mouse sensory neurones

The tetrodotoxin‐resistant (TTX‐r) persistent Na + current, attributed to Na V 1.9, was recorded in small (< 25 μm apparent diameter) dorsal root ganglion (DRG) neurones cultured from P21 rats and from adult wild‐type and Na V 1.8 null mice. In conventional whole‐cell recordings intracellular GTP‐γ‐S caused current up‐regulation, an effect inhibited by the PKC pseudosubstrate inhibitor, PKC19–36. The current amplitude was also up‐regulated by 25 μ m 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. PGE 2 did not acutely up‐regulate the current. Conversely, both PGE 2 and PKA activation up‐regulated the major TTX‐r Na + current, Na V 1.8. Extracellular ATP up‐regulated the persistent current with an average apparent K d near 13 μ m , 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.