title: Activation of CaMKII and ERK1/2 contributes to the time-dependent potentiation of Ca2+ response elicited by repeated application of capsaicin in rat DRG neurons.
abstract: When capsaicin is applied repeatedly to dorsal root ganglion (DRG) neurons for brief periods (10-15 s) at short intervals (5-10 min), the evoked responses rapidly decline, a phenomenon termed tachyphylaxis. In addition to this phenomenon, the present study using Ca(2+) imaging revealed that repeated application of capsaicin to rat dissociated DRG neurons at longer intervals (20-40 min) or during multiple applications at short intervals elicited an enhancement of the responses, termed potentiation. The potentiation occurred in 50-60% of the capsaicin-responsive cells, on average representing a 20- to 30% increase in the peak amplitude of the Ca(2+) signal, and was maximal at a 40-min application interval. An analysis of the mechanisms underlying potentiation revealed that it was suppressed by block of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) with 5 μM KN-93 or block of the activation of extracellular signal-regulated kinase (ERK) 1/2 with 2 μM U-0126. Lowering the extracellular Ca(2+) concentration from 2 to 1 mM or pretreatment with deltamethrin (1 μM), which blocks calcineurin and tachyphylaxis, enhanced potentiation. Potentiation was not affected by: 1) inhibition of protein kinase C or protein kinase A, 2) block of the three subtypes of neurokinin receptors, or 3) block of the trafficking of transient receptor potential V1 channel to the membrane. These results indicate that the potentiation is a slowly developing Ca(2+)-modulated process that is mediated by a complex intracellular signaling pathway involving activation of CaMKII and ERK1/2. Potentiation may be an important peripheral autosensitization mechanism that occurs independently of the pronociceptive effects of inflammatory mediators and neurotrophic factors.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pennsylvania, USA. xiz50@pitt.edu
authors.forename: Xiulin
authors.initials: X
authors.lastname: Zhang
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Daugherty
authors.forename: William C
authors.initials: WC
authors.lastname: de Groat
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011722:Pyrethrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D018689:Sensory System Agents / Q000494:pharmacology*; D013373:Substance P / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism; D013618:Tachyphylaxis; D013997:Time Factors; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002070:Butadienes; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002211:Capsaicin; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009570:Nitriles; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D011722:Pyrethrins; D018689:Sensory System Agents; D013373:Substance P; D013449:Sulfonamides; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C113580:U 0126; C072105:KN 93; D000096926:Benzenesulfonamides; C017180:decamethrin