Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain

<p>Abstract</p> <p>Background</p> <p>Major depression is a serious mood disorder affecting millions of adults and children worldwide. While the etiopathology of depression remains obscure, antidepressant medications increase synaptic levels of monoamine neurotransmitters in brain regions associated with the disease. Monoamine transmitters activate multiple signaling cascades some of which have been investigated as potential mediators of depression or antidepressant drug action. However, the diacylglycerol arm of phosphoinositide signaling cascades has not been systematically investigated, even though downstream targets of this cascade have been implicated in depression. With the ultimate goal of uncovering the primary postsynaptic actions that may initiate cellular antidepressive signaling, we have examined the antidepressant-induced production of CDP-diacylglycerol which is both a product of diacylglycerol phosphorylation and a precursor for the synthesis of physiologically critical glycerophospholipids such as the phosphatidylinositides. For this, drug effects on [³H]cytidine-labeled CDP-diacylglycerol and [³H]inositol-labeled phosphatidylinositides were measured in response to the tricyclics desipramine and imipramine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, the atypical antidepressants maprotiline and nomifensine, and several monoamine oxidase inhibitors.</p> <p>Results</p> <p>Multiple compounds from each antidepressant category significantly stimulated [³H]CDP-diacylglycerol accumulation in cerebrocortical, hippocampal, and striatal tissues, and also enhanced the resynthesis of inositol phospholipids. Conversely, various antipsychotics, anxiolytics, and non-antidepressant psychotropic agents failed to significantly induce CDP-diacylglycerol or phosphoinositide synthesis. Drug-induced CDP-diacylglycerol accumulation was independent of lithium and only partially dependent on phosphoinositide hydrolysis, thus indicating that antidepressants can mobilize CDP-diacylglycerol from additional pools lying outside of the inositol cycle. Further, unlike direct serotonergic, muscarinic, or α-adrenergic agonists that elicited comparable or lower effects on CDP-diacylglycerol versus inositol phosphates, the antidepressants dose-dependently induced significantly greater accumulations of CDP-diacylglycerol.</p> <p>Conclusion</p> <p>Chemically divergent antidepressant agents commonly and significantly enhanced the accumulation of CDP-diacylglycerol. The latter is not only a derived product of phosphoinositide hydrolysis but is also a crucial intermediate in the biosynthesis of several signaling substrates. Hence, altered CDP-diacylglycerol signaling might be implicated in the pathophysiology of depression or the mechanism of action of diverse antidepressant medications.</p

The Sec14-superfamily and the regulatory interface between phospholipid metabolism and membrane trafficking

A central principle of signal transduction is the appropriate control of the process so that relevant signals can be detected with fine spatial and temporal resolution. In the case of lipid-mediated signaling, organization and metabolism of specific lipid mediators is an important aspect of such control. Herein, we review the emerging evidence regarding the roles of Sec14-like phosphatidylinositol transfer proteins (PITPs) in the action of intracellular signaling networks; particularly as these relate to membrane trafficking. Finally, we explore developing ideas regarding how Sec14-like PITPs execute biological function. As Sec14-like proteins define a protein superfamily with diverse lipid (or lipophile) binding capabilities, it is likely these under-investigated proteins will be ultimately demonstrated as a ubiquitously important set of biological regulators whose functions influence a large territory in the signaling landscape of eukaryotic cells

Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain-0

<p><b>Copyright information:</b></p><p>Taken from "Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain"</p><p>http://www.biomedcentral.com/1471-2202/9/12</p><p>BMC Neuroscience 2008;9():12-12.</p><p>Published online 24 Jan 2008</p><p>PMCID:PMC2245968.</p><p></p>IMI), desipramine (DES), fluoxetine (FLU), paroxetine (PAR), maprotiline (MAP), or nomifensine (NOM). After 90 min, tissue contents of [H]CDP-diacylglycerol were assayed. Each bar is the mean ± SEM (N = 9). Each drug stimulated significant concentration-dependent accumulations of CDP-diacylglycerol (ANOVA, p < 0.001 for each drug). Based on Dunnett tests, all agents induced statistically significant CDP-diacylglycerol responses at the 3 or 10 μM concentrations, except for paroxetine in the hippocampus and imipramine in the striatum where the drug effects were not significant until the 30 μM and higher concentrations

Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain-6

<p><b>Copyright information:</b></p><p>Taken from "Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain"</p><p>http://www.biomedcentral.com/1471-2202/9/12</p><p>BMC Neuroscience 2008;9():12-12.</p><p>Published online 24 Jan 2008</p><p>PMCID:PMC2245968.</p><p></p>oncentrations of fluoxetine or imipramine were added, and after 60 min accumulated [H]CDP-diacylglycerol was measured. While the frontal cortex data are shown, similar observations were made in the hippocampus. Each bar is the mean ± SEM (= 6). The presence of LiCl did not significantly alter the stimulatory effects of fluoxetine or imipramine on [H]DCP- diacylglycerol accumulation (ANOVA, p > 0.05)

Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain-1

<p><b>Copyright information:</b></p><p>Taken from "Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain"</p><p>http://www.biomedcentral.com/1471-2202/9/12</p><p>BMC Neuroscience 2008;9():12-12.</p><p>Published online 24 Jan 2008</p><p>PMCID:PMC2245968.</p><p></p>IMI), desipramine (DES), fluoxetine (FLU), paroxetine (PAR), or maprotiline (MAP). After 90 min, [H]inositol phospholipids were extracted and assayed as a total pool of extractable phosphatidylinositides. Each bar is the mean ± SEM (N = 9). Each drug stimulated significant and concentration-dependent increases in [H]inositol phospholipid synthesis (ANOVA, p < 0.001 for each drug). From the subsequent Dunnett tests, all agents induced statistically significant CDP-diacylglycerol responses at the 3 or 10 μM and higher concentrations

Trans-Golgi Network and Endosome Dynamics Connect Ceramide Homeostasis with Regulation of the Unfolded Protein Response and TOR Signaling in Yeast

Synthetic genetic array analyses identify powerful genetic interactions between a thermosensitive allele (sec14-1ts) of the structural gene for the major yeast phosphatidylinositol transfer protein (SEC14) and a structural gene deletion allele (tlg2Δ) for the Tlg2 target membrane-soluble N-ethylmaleimide-sensitive factor attachment protein receptor. The data further demonstrate Sec14 is required for proper trans-Golgi network (TGN)/endosomal dynamics in yeast. Paradoxically, combinatorial depletion of Sec14 and Tlg2 activities elicits trafficking defects from the endoplasmic reticulum, and these defects are accompanied by compromise of the unfolded protein response (UPR). UPR failure occurs downstream of Hac1 mRNA splicing, and it is further accompanied by defects in TOR signaling. The data link TGN/endosomal dynamics with ceramide homeostasis, UPR activity, and TOR signaling in yeast, and they identify the Sit4 protein phosphatase as a primary conduit through which ceramides link to the UPR. We suggest combinatorial Sec14/Tlg2 dysfunction evokes inappropriate turnover of complex sphingolipids in endosomes. One result of this turnover is potentiation of ceramide-activated phosphatase-mediated down-regulation of the UPR. These results provide new insight into Sec14 function, and they emphasize the TGN/endosomal system as a central hub for homeostatic regulation in eukaryotes

Functional Anatomy of Phospholipid Binding and Regulation of Phosphoinositide Homeostasis by Proteins of the Sec14 Superfamily

Sec14, the major yeast phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer protein, regulates essential interfaces between lipid metabolism and membrane trafficking from the trans-Golgi network (TGN). How Sec14 does so remains unclear. We report that Sec14 binds PtdIns and PtdCho at distinct (but overlapping) sites, and both PtdIns- and PtdCho-binding activities are essential Sec14 activities. We further show both activities must reside within the same molecule to reconstitute a functional Sec14 and for effective Sec14-mediated regulation of phosphoinositide homeostasis in vivo. This regulation is uncoupled from PtdIns-transfer activity and argues for an interfacial presentation mode for Sec14-mediated potentiation of PtdIns kinases. Such a regulatory role for Sec14 is a primary counter to action of the Kes1 sterol-binding protein that antagonizes PtdIns 4-OH kinase activity in vivo. Collectively, these findings outline functional mechanisms for the Sec14 superfamily and reveal additional layers of complexity for regulating phosphoinositide homeostasis in eukaryotes. © 2008 Elsevier Inc. All rights reserved