Prostaglandin E2-induced sensitization of bradykinin-evoked responses in rat dorsal root ganglion neurons is mediated by cAMP-dependent protein kinase A.
Primary cultures of neonatal rat dorsal root ganglion (DRG) neurons were used to examine the mechanisms underlying both the direct activation and the sensitization of sensory neurons by prostanoids. Prostaglandin E2 (PGE2) elevated cytosolic calcium concentration ([Ca2+]i) in a subpopulation of small (< 19 microm) diameter, capsaicin-sensitive DRG neurons. PGE2 also stimulated substance P (SP) release from DRG cultures. In contrast to bradykinin, PGE2 did not stimulate phosphoinositidase C (PIC) and the PGE2-evoked increase in [Ca2+]i was dependent on extracellular calcium. Pre-treatment with PGE2 potentiated bradykinin-evoked increases in [Ca2+]i in small diameter neurons and increased the number of cells that responded to low concentrations of bradykinin. A similar effect was seen with prostaglandin I2 (PGI2) but not prostaglandin F2alpha (PGF2alpha). PGE2 pretreatment also potentiated bradykinin-evoked release of SP, inducing a leftward shift in the bradykinin concentration-response curve and an increase in the maximum response. PGE2 stimulated adenylyl cyclase activity in DRG cultures, at concentrations and times consistent with those required to observe both the direct and sensitizing effects of the prostanoid on [Ca2+]i responses. Furthermore, the direct and sensitizing effects of PGE2, on both [Ca2+]i responses and SP release, were mimicked by the membrane permeant cAMP analogue dibutyryl cAMP and inhibited by H89, an inhibitor of cAMP-dependent protein kinase A (PKA). These observations are consistent with the hypothesis that both direct activation and sensitization of sensory neurons by prostanoids, such as PGE2, are mediated by PKA-dependent phosphorylation mechanisms.
Smith
J A
JA
Novartis Institute for Medical Science, 5 Gower Place, London WC1E 6BN, UK.
Davis
C L
CL
Burgess
G M
GM
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D003994:Bucladesine / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000378:metabolism; D013449:Sulfonamides; D014316:Tritium
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; D014316:Tritium; D005576:Colforsin; D013373:Substance P; D003994:Bucladesine; D015544:Inositol 1,4,5-Trisphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D001920:Bradykinin; D002118:Calcium