Differential effects of antidepressants escitalopram versus lithium on Gs alpha membrane relocalization

Abstract

BackgroundPlasma membrane localization can play a significant role in the ultimate function of certain proteins. Specific membrane domains like lipid rafts have been shown to be inhibitory domains to a number of signaling proteins, including Gsα, and chronic antidepressant treatment facilitates Gs signaling by removing Gsα form lipid rafts. The intent of this study is to compare the effects of the selective serotnin reuptake inhibitor, escitalopram, with that of the mood stabilizing drug, lithium.ResultsThere are a number of mechanisms of action proposed for lithium as a mood stabilizing agent, but the interactions between G proteins (particularly Gs) and mood stabilizing drugs are not well explored. Of particular interest was the possibility that there was some effect of mood stabilizers on the association between Gsα and cholesterol-rich membrane microdomains (lipid rafts), similar to that seen with long-term antidepressant treatment. This was examined by biochemical and imaging (fluorescence recovery after photobleaching: FRAP) approaches. Results indicate that escitalopram was effective at liberating Gsα from lipid rafts while lithium was not.ConclusionsThere are a number of drug treatments for mood disorders and yet there is no unifying hypothesis for a cellular or molecular basis of action. It is evident that there may in fact not be a single mechanism, but rather a number of different mechanisms that converge at a common point. The results of this study indicate that the mood stabilizing agent, lithium, and the selective serotonin reuptake inhibitor, escitalopram, act on their cellular targets through mutually exclusive pathways. These results also validate the hypothesis that translocation of Gsα from lipid rafts could serve as a biosignature for antidepressant action.

Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression

“…These studies are also in agreement with observations that rolipram, a cAMPphosphodiesterase inhibitor, has antidepressant effects [172]. On the other hand, mood stabilizers lithium and valproate have the opposite effect, causing increased Gα s in lipid microdomains [173], thus suggesting a biphasic effect at the molecular level for treatment of the two "poles" of bipolar illness. Among monoaminergic receptors, D 1 and D 3 , 5-HT 7 , and β1-AR and β2-AR are known to couple with Gα s and cause increased cAMP, although only D 1 , 5-HT 7 , and β2-AR co-localize predominantly in lipid raft fractions.…”

Linoleic acid: Is this the key that unlocks the quantum brain? Insights linking broken symmetries in molecular biology, mood disorders and personalistic emergentism

“…The results of the authors’ experiments seem very consistent with those obtained on G proteins associated with –plasma membrane lipid rafts delineated by the group of Rasenick et al [42] as well as with the observations that the antibipolar drugs lithium and valproate, do not behave in a manner similar to antidepressants with regard to mobility of Gsα from lipid rafts [48]. The cell membrane lives, therefore, a constant condition of mobility, and, when the oscillations of fatty acids cross the tolerance ranges of the same, can be expressed pathological phenomena.…”

Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology

“…The changed fluidity appeared to be not due to direct interaction of the lithium with the membrane but rather to metabolic effects of lithium that, over course of the lithium treatment, altered the saturation of the lipid chains in the membrane. A more recent study utilizing C6 glioma cells indicates that the distribution of the signal protein GS alpha is moved into lipid rafts by lithium (Donati et al 2015 ). It is not clear whether this reorganization of the membrane was due to direct effect of lithium or due to lithium-induced metabolic changes that modified the membrane composition.…”