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 mum 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-gamma-S caused current up-regulation, an effect inhibited by the PKC pseudosubstrate inhibitor, PKC19-36. The current amplitude was also up-regulated by 25 microM 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 microM, 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.
Baker
Mark D
MD
Molecular Nociception Group, Department of Biology, Medawar Building, University College London, UK. mark.baker@ucl.ac.uk
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D003198:Computer Simulation; D005727:Ganglia, Spinal / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D008954:Models, Biological; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D013779:Tetrodotoxin; D015854:Up-Regulation
D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin; D000255:Adenosine Triphosphate; D012964:Sodium; D011493:Protein Kinase C