Muscarinic Modulation of Sodium Current by Activation of Protein Kinase C in Rat Hippocampal Neurons

Abstract

Phosphorylation of brain Na+ channels by protein kinase C (PKC) decreases peak Na+ current and slows macroscopic inactivation, but receptor-activated modulation of Na+ currents via the PKC pathway has not been demonstrated. We have examined modulation of Na+ channels by activation of muscarinic receptors in acutely-isolated hippocampal neurons using whole-cell voltage-clamp recording. Application of the muscarinic agonist carbachol reduced peak Na+ current and slowed macroscopic inactivation at all potentials, without changing the voltage-dependent properties of the channel. These effects were mediated by PKC, since they were eliminated when the specific PKC inhibitor (PKCI19-36) was included in the pipette solution and mimicked by the extracellular application of the PKC activator, OAG. Thus, activation of endogenous muscarinic receptors on hippocampal neurons strongly modulates Na+ channel activity by activation of PKC. Cholinergic input from basal forebrain neurons may have this effect in the hippocampus in vivo.

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

“…Similarly, we found that application of 0.5 μM Ro-31-8425 application blocked an increase in Nav1.8 currents induced by either 8-Br-cAMP or the cAMP analogue forskolin [23]. This was supported by the fact that application of a PKC inhibitor (staurosporine or PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] ) caused a marked inhibition of the forskolin-induced increase in the G V1/2 base (i.e. the percentage change in G at baseline V 1/2 ) [24,36,46].…”

“…The application of the PKC inhibitor PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] significantly suppresses the forskolin-induced increase in the Nav1.8 current but the PKA inhibitor WIPTIDE has no significant effect on the PKC activator phorbol12, 13-dibutyrate (PDBu)-induced increase in the current [36]. When considering these results together, it is possible that PKCinduced phosphorylation of the channel protein at serine 1506 is required to enable PKA-induced phosphorylation of other sites on the channel protein suggested by Li et al [40] in a relationship between PKC and PKA on the convergent regulation of Na + channels.…”

“…The slow onset of Nav1.9 channel opening probably implies that this type of Na + channels makes a minor contribution to the action potential amplitude [25]. The majority of voltage-gated sodium channels (VGSCs) are inhibited by either protein kinase C (PKC) or protein kinase A (PKA) [26][27][28][29][30][31][32]. The VGSC into the skeletal and cardiac muscles is not significantly affected by the activation of PKA [33,34].…”

Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

“…Cerebellar Purkinje neurons were acutely dissociated from P13-P14 mice using procedures modified from those of Cantrell et al (1996) and . Animals were deeply anesthetized with halothane before decapitation.…”

The effects of cholinergic neuromodulation on neuronal phase-response curves of modeled cortical neurons

“…To mimic high concentrations, we changed E leak =−60 to −58 mV, g leak =2×10 −5 to 1.8×10 −5 S cm −2 , g KM =2×10 −4 to 10 −3 Scm −2 . Cantrell et al (1996) reported a significant muscarinic acetylcholine-receptor mediated down-regulation of sodium current conductance. Interestingly, they found two populations of neurons, in which this current was reduced to 90% and 55%, respectively.…”