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J. Biol. Chem., Vol. 276, Issue 14, 10888-10896, April 6, 2001
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From the Recent data suggest that
Protein Kinase Inhibition by
-3 Fatty Acids*
,,, and¶
Division of Neuroscience and the
§ Department of Psychiatry and Behavioral Sciences, Baylor
College of Medicine, Houston, Texas 77030
-3 fatty acids may be
effective in epilepsy, cardiovascular disorders, arthritis, and
as mood stabilizers for bipolar disorder; however, the mechanism of
action of these compounds is unknown. Based on earlier studies
implicating -3 fatty acids as inhibitors of protein kinase C
activity in intact cells, we hypothesized that -3 fatty acids may
act through direct inhibition of second messenger-regulated kinases and
sought to determine whether the -3 double bond might uniquely confer
pharmacologic efficacy and potency for fatty acids of this type. In our
studies we observed that -3 fatty acids inhibited the in
vitro activities of cAMP-dependent protein kinase,
protein kinase C, Ca2+/calmodulin-dependent protein kinase
II, and the mitogen-activated protein kinase (MAPK). Our results
with a series of long-chain fatty acid structural homologs suggest an
important role for the -3 double bond in conferring inhibitory
efficacy. To assess whether -3 fatty acids were capable of
inhibiting protein kinases in living neurons, we evaluated their effect
on signal transduction pathways in the hippocampus. We found that -3
fatty acids could prevent serotonin receptor-induced MAPK activation in
hippocampal slice preparations. In addition, we evaluated the effect of
-3 fatty acids on hippocampal long-term potentiation, a form of
synaptic plasticity known to be dependent on protein kinase activation. We observed that -3 fatty acids blocked long-term
potentiation induction without inhibiting basal synaptic transmission.
Overall, our results from both in vitro and live
cell preparations suggest that inhibition of second messenger-regulated
protein kinases is one locus of action of -3 fatty acids.
*
This work was supported by grants from the National
Institutes of Health, NARSAD, and the Texas Advanced Technology
Program.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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