British Journal of Anaesthesia, Vol 78, Issue 2 189-196, Copyright © 1997 by The Board of Management and Trustees of the British Journal of Anaesthesia
H. C. Hemmings Jr and AIB. Adamo
Protein kinase C (PKC) is a key regulatory enzyme that has been implicated
as a molecular target for the action of general anaesthetics. We have
determined the effects of halothane on the translocation and
down-regulation of conventional PKC (cPKC) by analysing the subcellular
distribution of PKC activity, [3H]phorbol- 12,13-dibutyrate ([3H]PDBu)
binding and PKC immunoreactivity in intact rat cerebrocortical
synaptosomes, a subcellular fraction that contains functional nerve
terminals. Halothane alone (2.4 vol%) reduced membrane- associated (P <
0.05) and increased cytosol (P < 0.01) PKC activity, while
phorbol-12-myristate, 13-acetate (PMA) 0.1 mumol litre-1, a metabolically
stable activator of PKC, reduced membrane (P < 0.01) without altering
cytosol PKC activity. Halothane and PMA in combination reduced membrane PKC
activity to undetectable levels and reduced cytosol PKC activity (P <
0.01). Halothane alone had no significant effects on the distribution of
[3H]PDBu binding, while PMA alone significantly reduced both membrane and
cytosol [3H]PDBu binding (P < 0.01). Halothane and PMA in combination
reduced membrane and cytosol [3H]PDBu binding further, but this effect was
not significantly different from the effect of PMA alone. Experiments using
isoform- selective antibodies to PKC alpha, PKC beta or PKC gamma
demonstrated synergistic interactions between halothane and PMA in
promoting translocation of the three conventional PKC isoforms from the
cytosol to the membrane fraction of synaptosomes and down-regulation of
their immunoreactivity. Halothane and PMA together reduced cytosol PKC
alpha/beta/gamma immunoreactivity significantly more (P < 0.05) than PMA
alone. Halothane thus has two distinct actions on PKC in synaptosomes:
activation of endogenous PKC activity and potentiation of
activation-induced cPKC translocation and down-regulation. These
potentially competing effects may underlie some of the conflicting results
obtained with halothane on PKC-mediated processes in intact cells.
LABORATORY INVESTIGATIONS
Effect of halothane on conventional protein kinase C translocation and down-regulation in rat cerebrocortical synaptosomes
Department of Anesthesiology, Cornell University Medical College, New York, NY 1002, USA
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