Effects of PKC and PKA Inhibitors on the cAMP-Stimulant-Induced Enhancement of Tetrodotoxin-Resistant Na + (Nav1.8) Currents

Abstract

The protein kinase C (PKC) inhibitor bisindolymaleimide Ro-31-8425 (Ro-31-8425) decreases the peak tetro- dotoxin-resistant (TTX-R) Na + (Nav1.8) current in nodose ganglion (NG) neurons, and this decrease is not altered by si- multaneous application of 8-bromo-cAMP (8-Br-cAMP), phorbol 12-myristate 13-acetate (PMA, a PKC activator) or forskolin (a cAMP analogue). Intracellular application of the endogenous protein kinase A (PKA) inhibitor, protein kinase inhibitor (PKI) abolishes the increase in the peak Nav1.8 current that occurs in response to the applications of 8-Br- cAMP, PMA, forskolin, or prostaglandin E2 (PGE2, an adenyl cyclase activator). At a higher concentration (0.5 mM) compared with a sufficient concentration (0.01 mM) to block the cAMP-stimulant Nav1.8 current, PKI still attenuated the Ro-31-8425-induced decrease in peak Nav1.8 current. When we considered these results together, cAMP-stimulant- induced modification of Nav1.8 currents is mediated by the activation of both PKA and PKC, and PKC may be located upstream of PKA.