title: Protein kinase inhibition by omega-3 fatty acids.
abstract: Recent data suggest that omega-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 omega-3 fatty acids as inhibitors of protein kinase C activity in intact cells, we hypothesized that omega-3 fatty acids may act through direct inhibition of second messenger-regulated kinases and sought to determine whether the omega-3 double bond might uniquely confer pharmacologic efficacy and potency for fatty acids of this type. In our studies we observed that omega-3 fatty acids inhibited the in vitro activities of cAMP-dependent protein kinase, protein kinase C, Ca(2+)/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 omega-3 double bond in conferring inhibitory efficacy. To assess whether omega-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 omega-3 fatty acids could prevent serotonin receptor-induced MAPK activation in hippocampal slice preparations. In addition, we evaluated the effect of omega-3 fatty acids on hippocampal long-term potentiation, a form of synaptic plasticity known to be dependent on protein kinase activation. We observed that omega-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 omega-3 fatty acids.
authors.affiliation: Division of Neuroscience, Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mirnikjoo
authors.forename: S E
authors.initials: SE
authors.lastname: Brown
authors.forename: H F
authors.initials: HF
authors.lastname: Kim
authors.forename: L B
authors.initials: LB
authors.lastname: Marangell
authors.forename: J D
authors.initials: JD
authors.lastname: Sweatt
authors.forename: E J
authors.initials: EJ
authors.lastname: Weeber
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D015525:Fatty Acids, Omega-3; D011494:Protein Kinases