Modulation of TTX-RINaby PKC and PKA and Their Role in PGE2-Induced Sensitization of Rat Sensory NeuronsIn Vitro

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Abstract
A tetrodotoxin-resistant voltage-gated Na+current (TTX-RINa) 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-RINaare still being defined. We have examined the modulation of TTX-RINain isolated sensory neurons with whole-cell voltage-clamp recording. Activation of either PKC or PKA increased TTX-RINa. PKA activation also produced a leftward shift in the conductance–voltage relationship of TTX-RINaand an increase in the rates of current activation, deactivation, and inactivation. Inhibitors of PKC decreased TTX-RINa, 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-RINa, inhibitors of PKC significantly attenuated PKA-induced modulation of the current. Finally, although PGE2-induced modulation of TTX-RINawas 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-RINais 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-RINa.