Journal of Neuroscience, Vol 8, 2606-2617, Copyright © 1988 by Society for Neuroscience
Depolarization of nonmyelinated fibers of the rat vagus nerve produced by activation of protein kinase C
HP Rang and JM Ritchie
Sandoz Institute for Medical Research, London, England.
The effect of activation of protein kinase C by phorbol esters has been
studied on the nonmyelinated (C) fibers of the rat vagus nerve. Grease- gap
recording at room temperature was used to monitor changes in the resting
and action potentials. Effects of phorbol esters on the rate of efflux of
86Rb and 14C-guanidinium were also measured. The active isomer beta-phorbol
12,13-dibutyrate (PDBu), applied for 10 min at concentrations of 10 nM to 3
microM, caused a slowly developing depolarization, which persisted after
the drug was washed out. The action potential was concomitantly reduced.
These effects did not occur with the inactive isomer alpha-phorbol
12,13-didecanoate. The PDBu- induced depolarization was reduced by about
75% if Na+ was replaced by the impermeant cation N-methyl-(+)-glucamine
(NMG); the residual effect was almost abolished if the nerves were
presoaked in a solution containing gluconate in place of Cl-. It was
concluded that increases in conductance mainly to Na+ and Cl- were
responsible for the depolarization. The response was unaffected by
tetrodotoxin or calcium- channel blockers. Omission of Ca2+, surprisingly,
enhanced the PDBu- induced depolarization 3-5-fold; furthermore, addition
of 2 mM Ca2+ following a PDBu-induced depolarization recorded in Ca2+-free
solution caused a pronounced repolarization. This effect of Ca2+ occurred
also with Sr2+ and Ba2+, but not with other divalent cations or with La3+.
Divalent cations known to block Ca channels inhibited the repolarizing
action of Ca2+. These results suggested that Ca2+ acts intracellularly,
either to block Na channels opened by PDBu or to activate protein
phosphatases. The PDBu-induced response in Ca2+-free solution was increased
2-fold by a reduction in pH from 7.4 to 6.5. Under normal conditions the
nerve was reversibly depolarized by this pH change; after PDBu this pH
sensitivity was enhanced, and depolarization occurred at a less acidic pH.
PDBu caused a 3-4-fold increase in the rate of efflux of 86Rb (a marker for
K+ ions) and of 14C-guanidinium (a marker for Na+ ions) from preloaded
nerves. These effects, in contrast to the depolarization, were
transient.(ABSTRACT TRUNCATED AT 400 WORDS)
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