G-Protein Signaling, Lipid Rafts and the Possible Sites of Action for the Antidepressant Effects of n-3 Polyunsaturated Fatty Acids

Abstract

Dietary fish oil, a source of polyunsaturated fatty acids (n-3 PUFA), has become increasingly popular for antidepressant therapy, in part because about half of patients treated with conventional antidepressants either fail to remit or discontinue therapy due to side effects. The inception of n-3 PUFA as a putative depression therapeutic may have stemmed from reports suggesting that dietary n-3 PUFA deficiency is linked to both altered membrane PUFA content as well as clinical depression. Several studies have examined n-3 PUFA treatment in depression, either singly or in combination with conventional antidepressant drugs. While results have been encouraging, fish oil treatment remains controversial. At least some of the reason for this is the lack of a defined site of action for n-3 PUFA that would be consistent with an antidepressant effect. This review will address this issue. While it is possible, even likely, that n-3 PUFA have multiple sites of action, this chapter will focus on sites at which n-3 PUFA modify G protein signaling and how those sites relate to both depression and antidepressant action. Much of the focus herein will be on specialized membrane domains (lipid rafts) and the effects that agents modifying those rafts have on elements of G protein signaling cascades. The relevance of specific alterations of G protein signaling for both depression and antidepressant action will be discussed, as will the ability for n-3 PUFA to act either as an antidepressant or in concert with conventional antidepressants.

Fish oil and depression: The skinny on fats

“…Since escitalopram and R-citalopram have equal lipophilicity, there is likely a lipid raft protein that acts as a binding site for antidepressants. This study also revealed that antidepressant accumulation in rafts is a slow process mirroring the time course for the invitro effects of these drugs [9,16,69]. Similarly, published findings analyzing the components of raft and non-raft membrane samples show that DHA is present in both [54].…”

“…While this study did not examine heterotrimeric G proteins, a similar effect of PUFA is certainly possible. Furthermore, PUFAs are able to affect fatty acylation of several signaling proteins [8,9,17,20,49]. …”

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

“…studies, however, suggest that PR3 has a greater role than NE in IL-1β processing and secretion. (3) PR3 is localized in the same lipid raft domains (75,76) as A1AT (5,20) and LA (77). Bilayer-bound PR3 has a reduced catalytic efficiency, whereas its inhibition by A1AT is more important than that observed for the soluble form of the enzyme.…”

The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for the Treatment of Depression, PTSD, and Suicidal Behaviors

“…In addition, several reports indicate that lower ω3-fatty-acid levels, including lower plasma EPA, and DHA, or EPA in red blood cells, predicted greater risk of suicide attempt (Hibbeln and Salem, 1995, Huan et al , 2004, Sublette et al , 2006). Because both cholesterol and DHA are major components of the lipid raft, it is possible that reduced cholesterol and ω3-fatty-acid levels may affect the formation of lipid rafts in the CNS, and subsequently reduce neurotransmitter signaling (Czysz and Rasenick, 2013). Notably, increased formation of lipid rafts in the membrane would facilitate serotonergic (Donati et al , 2008, Renner et al , 2007), dopaminergic (Villar et al ., 2009), and glutamatergic (Francesconi et al , 2009, Ponce et al , 2008) neurotransmitter signaling; all of these play important roles in the pathophysiology and treatment of psychiatric disorders.…”