title: Up-regulation of low-threshold tetrodotoxin-resistant Na+ current via activation of a cyclic AMP/protein kinase A pathway in nociceptor-like rat dorsal root ganglion cells.
abstract: The effects of forskolin on low-threshold tetrodotoxin-resistant (TTX-r) Na(+) currents was studied in small diameter (average ≈ 25 μm) dorsal root ganglion (DRG) cells. All DRG cells included in the study were categorized as type-2 or non-type-2 based on the expression of a low-threshold A-current. In all type-2 and some non-type-2 DRG cells held at -80 mV, the adenylyl cyclase (AC) activator forskolin (10 μM) up-regulated TTX-r Na(+) currents evoked with steps to -55 mV through -35 mV (low-threshold current). Up-regulation of low-threshold current by forskolin was mimicked by the protein kinase A (PKA) agonist Sp-cAMPs and the inflammatory mediator serotonin, and blocked by the PKA antagonist Rp-cAMPs. Forskolin-induced up-regulation of low-threshold current evoked from a holding potential of -60 mV was blocked by 40 ms steps to 0 mV, which presumably induced a long lasting inactivation of the low-threshold channels. Reducing to 3 ms the duration of steps to 0 mV, significantly increased the number of DRG cells where low-threshold current was up-regulated by forskolin, presumably by reducing the long-lasting inactivation of the low-threshold channels. In the same cells, high-threshold current, evoked by 40 ms or 3 ms steps to 0 mV, was consistently up-regulated by forskolin. The selective Na(V)1.8 channel blocker A-803467 markedly blocked high-threshold current but not low-threshold current. The different voltage protocols observed to activate and inactivate the low- and high-threshold currents, and the observation that A-803467 blocked high- but not low-threshold current suggests that the two currents were mediated by different channels, possibly Na(V)1.8 and Na(V)1.9, respectively. Inflammatory mediators may simultaneously up-regulate Na(V)1.8 and Na(V)1.9 channels in the same nociceptor via a AC/PKA signaling pathway, increasing nociceptor signaling strength, and lowering nociceptor threshold, respectively.
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. rscroggs@uthsc.edu
authors.forename: R S
authors.initials: RS
authors.lastname: Scroggs
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000096:biosynthesis* / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases