Protein Kinase Inhibition by ω-3 Fatty Acids

Abstract

Recent data suggest that -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 cAMPdependent protein kinase, protein kinase C, Ca 2؉ /calmodulin-dependent protein kinase II, and the mitogenactivated 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.

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

“…DHA increases PKC activity in macrophage cell lines, 65 but inhibits activity of isolated catalytic PKC subunits. 66 In the present study, there was no significant difference in total PKC activity, but an effect on PKC isoforms cannot be ruled out.…”

“…Exogenous DHA decreases cytosolic and particulate PKA activity in macrophage tumor cells (AK-5) 65 and decreases catalytic PKA activity in vitro. 66 In the current study, n-3 PUFA deprivation significantly increased basal PKA activity in the frontal cortex due to a loss of the inhibitory effect of DHA possibly. We also observed that the addition of DHA to rat primary cortical astrocytes decreased PKA activity.…”

Unsaturated Fatty Acids and Pain

“…In addition, n-3 PUFA intake blocks the activity of mitogen-activated protein kinase, 25) which is involved in the modulation of central sensitization induced by inflammatory and neuropathic pain, suggesting another potential pathway to inhibit pain transmission. 26,27) Interestingly, intake of a-linolenic acid, one of the n-3 PUFAs, has been reported to suppress the production of lysophosphatidic acid, a factor strongly related to the development of neuropathic pain. 28) Docosahexaenoic acid (DHA), one of the n-3 PUFAs, has a 22-carbon chain with six double bonds.…”

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

“…Oleic acid appears to affect indirectly TAM's dissociation from cellular antiestrogen binding sites (Hwang, 1987), an effect that could increase the intracellular concentrations of free drug. Since n-3 PUFAs have many biological activities, they may play a role in modifying TAM's actions, including an ability to inhibit protein kinases (Mirnikjoo et al, 2001). g-linolenic acid has several properties that might make it antitumorigenic.…”