title: Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro.
abstract: A tetrodotoxin-resistant voltage-gated Na+ current (TTX-R INa) appears to be the current primarily responsible for action potential generation in the cell body and terminals of nociceptive afferents. Although other voltage-gated Na+ currents are modulated by the activation of protein kinase C (PKC), protein kinase A (PKA), or both, the second messenger pathways involved in the modulation of TTX-R INa are still being defined. We have examined the modulation of TTX-R INa in isolated sensory neurons with whole-cell voltage-clamp recording. Activation of either PKC or PKA increased TTX-R INa. PKA activation also produced a leftward shift in the conductance-voltage relationship of TTX-R INa and an increase in the rates of current activation, deactivation, and inactivation. Inhibitors of PKC decreased TTX-R INa, whereas inhibitors of PKA had no effect on the current. Investigating the interaction between PKC and PKA revealed that although inhibitors of PKA had little effect on PKC-induced modulation of TTX-R INa, inhibitors of PKC significantly attenuated PKA-induced modulation of the current. Finally, although PGE2-induced modulation of TTX-R INa was more similar to PKA-induced modulation of the current than to PKC-induced modulation, PGE2-induced effects were inhibited by inhibitors of both PKC and PKA. Thus, although TTX-R INa is a common target for cellular processes involving the activation of either PKA or PKC, PKC activity is necessary to enable subsequent PKA-mediated modulation of TTX-R INa.
authors.affiliation: Department of Oral and Craniofacial Biological Sciences, University of Maryland, Baltimore Dental School, Baltimore, Maryland 21201, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Gold
authors.forename: J D
authors.initials: JD
authors.lastname: Levine
authors.forename: A M
authors.initials: AM
authors.lastname: Correa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D015232:Dinoprostone