Fig. 7.
Possible mechanisms underlying PKC-, PKA- and PGE2-induced modulation of TTX-RINa. Pathways clearly implicated by experimental evidence are represented by solid arrows. Pathways for which there is minimal experimental evidence are represented by dashed arrows. Protein kinase C (PKC) appears to be constitutively active in DRG neurons. Inhibition (−) of PKC results in a decrease (−) in the maximal conductance (Gmax) of TTX-RINa. Activation (+) of PKC increases (+) theGmax of TTX-RINa. That activation of PKC increases TTX-RINa suggests that stimuli (thermal and chemical) whose transduction pathways result in the activation of PKC may sensitize nociceptors via the modulation of TTX-RINa. Activation of PKA also increasesGmax of TTX-RINa, in addition to increasing the rates of current activation, inactivation, and deactivation and shifting the voltage-dependence of activation in a hyperpolarizing direction. Although the magnitude of PKA-induced changes in TTX-RINa are larger than PKC-induced changes in the current, PKC activity is necessary to enable PKA-induced modulation of TTX-R INa. PGE2-induced modulation of TTX-R INa involves the activation of PKA and is dependent on PKC activity. Several observations suggest that PGE2 may activate another second messenger pathway(s) in addition to that involving activation of PKA (see Results for details). One such pathway may involve activation of PKC in a feedback mechanism resulting in the attenuation of PGE2-induced effects. A second additional pathway may involve inhibition of adenylate cyclase, resulting in a decrease in PKA activity.