Activation of protein kinase C augments peptide release from rat sensory neurons.
To determine whether protein kinase C (PKC) mediates release of peptides from sensory neurons, we examined the effects of altering PKC activity on resting and evoked release of substance P (SP) and calcitonin gene-related peptide (CGRP). Exposing rat sensory neurons in culture to 10 or 50 nM phorbol 12,13-dibutyrate (PDBu) significantly increased SP and CGRP release at least 10-fold above resting levels, whereas the inactive 4alpha-PDBu analogue at 100 nM had no effect on release. Furthermore, 100 nM bradykinin increased peptide release approximately fivefold. Down-regulation of PKC significantly attenuated the release of peptides evoked by either PDBu or bradykinin. PDBu at 1 nM or 1-oleoyl-2-acetyl-sn-glycerol at 50 microM did not alter resting release of peptides, but augmented potassium- and capsaicin-stimulated release of both SP and CGRP approximately twofold. This sensitizing action of PKC activators on peptide release was significantly reduced by PKC down-regulation or by pretreating cultures with 10 nM staurosporine. These results establish that activation of PKC is important in the regulation of peptide release from sensory neurons. The PKC-induced enhancement of peptide release may be a mechanism underlying the neuronal sensitization that produces hyperalgesia.
Barber
L A
LA
Department of Pharmacology, Indiana University School of Medicine, Indianapolis, 46202-5120, USA.
Vasko
M R
MR
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured / Q000201:enzymology; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D051379:Mice; D009475:Neurons, Afferent / Q000166:cytology / Q000201:enzymology*; D009479:Neuropeptides / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013373:Substance P / Q000378:metabolism*
D002273:Carcinogens; D009479:Neuropeptides; D013373:Substance P; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D015740:Calcitonin Gene-Related Peptide; D011188:Potassium; D002211:Capsaicin; D001920:Bradykinin