Neurokinin 2 receptor-mediated activation of protein kinase C modulates capsaicin responses in DRG neurons from adult rats.
Patch-clamp techniques and Ca2+ imaging were used to examine the interaction between neurokinins (NK) and the capsaicin(CAPS)-evoked transient receptor potential vanilloid receptor 1 (TRPV1) responses in rat dorsal root ganglia neurons. Substance P (SP; 0.2-0.5 microM) prevented the reduction of Ca2+ transients (tachyphylaxis) evoked by repeated brief applications of CAPS (0.5 microM). Currents elicited by CAPS were increased in amplitude and desensitized more slowly after administration of SP or a selective NK2 agonist, [Ala8]-neurokinin A (4-10) (NKA). Neither an NK1-selective agonist, [Sar9, Met11]-SP, nor an NK3-selective agonist, [MePhe7]-NKB, altered the CAPS currents. The effects of SP on CAPS currents were inhibited by a selective NK2 antagonist, MEN10,376, but were unaffected by the NK3 antagonist, SB 235,375. Phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C(PKC), also increased the amplitude and slowed the desensitization of CAPS responses. Phosphatase inhibitors, decamethrin and alpha-naphthyl acid phosphate (NAcPh), also enhanced the currents and slowed desensitization of CAPS currents. Facilitatory effects of SP, NKA and PDBu were reversed by bisindolylmaleimide, a PKC inhibitor, and gradually decreased in magnitude when the agents were administered at increasing intervals after CAPS application. The decrease was partially prevented by prior application of NAcPh. These data suggest that activation of NK2 receptors in afferent neurons leads to PKC-induced phosphorylation of TRPV1, resulting in sensitization of CAPS-evoked currents and slower desensitization. Thus, activation of NK2 autoreceptors by NKs released from the peripheral afferent terminals or by mast cells during inflammatory responses may be a mechanism that sensitizes TRPV1 channels and enhances afferent excitability.
Sculptoreanu
Adrian
A
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. ads5@pitt.edu
Aura Kullmann
F
F
de Groat
William C
WC
D000367:Age Factors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D008297:Male; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D015287:Neurokinin B / Q000031:analogs & derivatives / Q000494:pharmacology; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2 / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism
D002273:Carcinogens; D010446:Peptide Fragments; D010703:Phorbol Esters; D018041:Receptors, Neurokinin-2; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C080394:neurokinin B, MePhe(7)-; C064218:neurokinin A (4-10), beta-Ala(8)-; D013373:Substance P; D015288:Neurokinin A; D015287:Neurokinin B; D011493:Protein Kinase C; D002211:Capsaicin; D002118:Calcium