Activation of protein kinase C by the capsaicin analogue resiniferatoxin in sensory neurones.
Resiniferatoxin and capsaicin are sensory neurone-specific excitotoxins that operate a common cation channel in nociceptors. Resiniferatoxin is structurally similar to capsaicin and to phorbol esters. Specific [3H]-resiniferatoxin binding, which was detected in the membrane (KD value 1.8 +/- 0.2 nM) but not cytosolic fraction of rat dorsal root ganglia, could not be displaced by phorbol 12,13-dibutyrate. Conversely, resiniferatoxin did not displace [3H]phorbol 12,13-dibutyrate binding in either the cytosolic or membrane fraction. Resiniferatoxin and capsaicin both caused translocation of protein kinase C in dorsal root ganglion neurones (EC50 value 18 +/- 3 nM). This translocation was greatly reduced but not abolished, in the absence of external Ca2+, suggesting that it was secondary to Ca2+ entry. Resiniferatoxin also caused direct activation of a Ca(2+)- and lipid-dependent kinase (or kinases) in the cytosolic fraction of dorsal root ganglia, at concentrations (100 nM to 10 microM) higher than required for displacement of [3H]resiniferatoxin binding or translocation of protein kinase C. Capsaicin (up to 10 microM) was unable to mimic this effect. These data imply that although resiniferatoxin-induced translocation of protein kinase C in dorsal root ganglion neurones was mainly indirect, it also caused direct activation of a protein kinase C-like kinase in these cells.
Harvey
J S
JS
Sandoz Institute for Medical Research, London, England, UK.
Davis
C
C
James
I F
IF
Burgess
G M
GM
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000201:enzymology* / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D004224:Diterpenes; D009498:Neurotoxins; D014316:Tritium; D015240:Phorbol 12,13-Dibutyrate; D015759:Ionomycin; D011189:Potassium Chloride; C024353:resiniferatoxin; D011493:Protein Kinase C; D002211:Capsaicin