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

Abstract

Abstract:The protein kinase C (PKC) inhibitor bisindolymaleimide ) decreases the peak tetrodotoxin-resistant (TTX-R) Na + (Nav1.8) current in nodose ganglion (NG) neurons, and this decrease is not altered by simultaneous 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-BrcAMP, PMA, forskolin, or prostaglandin E 2 (PGE 2, 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-stimulantinduced modification of Nav1.8 currents is mediated by the activation of both PKA and PKC, and PKC may be located upstream of PKA.

PKC Activation is Required for TSH-mediated Lipolysis via Perilipin Activation

“…It also remains to be determined whether this PKC eff ect on perilipin phosphorylation is direct, or indirect through an intermediary that in turn acts on perilipin, such as regulation of PKA. We observed a decrease in TSH-stimulated phospho-CREB levels by PKC inhibition, which is consistent with the possibility of PKA being a downstream target of PKC in human adipocytes as has been proposed in rat adipose tissue [ 30 ] and ganglion neurons [ 31 ] . More work is needed to fully delineate the mechanism underlying this PKC-dependent event.…”