Journal of Neuroscience, Vol 9, 473-479, Copyright © 1989 by Society for Neuroscience
Protein kinase inhibitors selectively block phorbol ester- or forskolin- induced changes in excitability of Aplysia neurons
PJ Conn, JA Strong, EM Azhderian, AC Nairn, P Greengard and LK Kaczmarek
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
Exposure of the bag cell neurons of Aplysia to activators of protein kinase
C, such as phorbol esters, enhances electrically evoked action potentials
by increasing the voltage-dependent calcium current. We have hypothesized
that this effect is mediated by the activation of protein kinase C (PKC).
An important prediction of this hypothesis is that inhibitors of PKC should
inhibit these phorbol ester-induced changes in bag cell neuronal
excitability. We have now found that treatment of bag cell neurons with the
protein kinase inhibitor 1-[5- isoquinolinesulfonyl]-2-methyl piperazine
(H-7) inhibits the phorbol ester-induced enhancement of bag cell action
potentials and prevents the enhancement of calcium current by phorbol
esters. The height and width of electrically evoked action potentials in
bag cell neurons can also be enhanced by cAMP analogs or agents that
elevate cAMP. These agents do not influence the major voltage-dependent
calcium current in the bag cell neurons but may act by modulating potassium
currents and other voltage-dependent currents. We have found that
microinjection of a protein inhibitor of cAMP-PK (PKA-I) into isolated bag
cell neurons prevents and reverses the effect of the adenylate cyclase
activator forskolin on action potentials of these cells. In contrast, H-7
does not inhibit the effects of forskolin on a variety of responses in
these cells, including its effects on action potentials, granule movement,
and 32P incorporation into phosphoproteins. This suggests that H-7 is
selective for PKC relative to cAMP-PK in intact bag cell neurons.
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