Modulation of TTX-R<i>I</i>_Naby PKC and PKA and Their Role in PGE₂-Induced Sensitization of Rat Sensory Neurons<i>In Vitro</i>

Abstract

A tetrodotoxin-resistant voltage-gated Na + current (TTX-R I Na ) 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 I Na are still being defined. We have examined the modulation of TTX-R I Na in isolated sensory neurons with whole-cell voltage-clamp recording. Activation of either PKC or PKA increased TTX-R I Na . PKA activation also produced a leftward shift in the conductance–voltage relationship of TTX-R I Na and an increase in the rates of current activation, deactivation, and inactivation. Inhibitors of PKC decreased TTX-R I Na , 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 I Na , inhibitors of PKC significantly attenuated PKA-induced modulation of the current. Finally, although PGE 2 -induced modulation of TTX-R I Na was more similar to PKA-induced modulation of the current than to PKC-induced modulation, PGE 2 -induced effects were inhibited by inhibitors of both PKC and PKA. Thus, although TTX-R I Na 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 I Na .