Antidepressants Produce Persistent G<i>α</i><sub>s</sub>-Associated Signaling Changes in Lipid Rafts after Drug Withdrawal

Senese, Nicolas B.; Rasenick, Mark M.

doi:10.1124/molpharm.120.000226

Cited by 8 publications

(13 citation statements)

References 68 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is post-mortem evidence that suggests that lipid rafts from subjects with MDD are enriched in the heterotrimeric G protein, Gsalpha (Gsα) consistent with diminished cAMP signaling ( 29 – 30 ). Gsα located outside lipid rafts stimulates adenylyl cyclase more efficiently than when it is located within lipid rafts and chronic treatment with antidepressants facilitates G protein exodus from those rafts ( 20 , 23 – 26 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

A novel peripheral biomarker for depression and antidepressant response

et al. 2022

Self Cite

View full text Add to dashboard Cite

In contrast to healthy controls, the heterotrimeric G protein, Gsalpha (Gsα) is ensconced predominantly in lipid rafts in subjects with major depressive disorder (MDD) resulting in impaired stimulation of adenylyl cyclase. In this small proof-of-concept study, we examined the hypothesis that translocation of Gsα from lipid rafts toward a more facile activation of adenylyl cyclase is a biomarker for clinical response to antidepressants. There were 49 subjects with MDD (HamD 17 score ≥15) and 59 healthy controls at the screen visit. The AlphaScreen (PerkinElmer) assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsα-adenylyl cyclase to assess the extent of coupling of Gsα with adenylyl cyclase. At screen, platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls (p = 0.02). Subsequently, 19 consenting MDD subjects completed a 6-week open label antidepressant treatment trial. The 11 antidepressant responders (HamD 17 improvement ≥50% from screen) revealed significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders (p = 0.05) with an effect size of 0.83 for the PGE1/Gsα lipid-raft biomarker. PGE1 stimulation increased by ≥30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%) [Fisher exact = 0.07] with a positive predictive value for response of 80.0%. In this small, pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects. These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed. Future studies are needed to evaluate the utility of this biomarker for the treatment of MDD.

show abstract

Section: Discussionmentioning

confidence: 99%

A novel peripheral biomarker for depression and antidepressant response

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mechanism (4) - Additional pathways are consistent with our experiments to the extent that they involve SSRIs within membranes. Such pathways include interactions with TRKB (Casarotto et al, 2021), lipid rafts (Senese and Rasenick, 2021), or lipid-modifying enzymes (Kornhuber and Gulbins, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…The LogP and LogD pH7.4 for escitalopram are ∼ 0.5 less than for fluoxetine, perhaps corresponding to part of the difference in accumulation. The difference between fluoxetine and escitalopram is unlikely to arise from drug efflux pumps (Peters et al, 2009) but could arise from one or more other mechanisms, including kinetics of partitioning into lipid rafts (Senese and Rasenick, 2021), lateral diffusion within the plane of the membrane, and effects on membrane elasticity and curvature (Kapoor et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Selective Serotonin Reuptake Inhibitors Within Cells: Temporal Resolution in Cytoplasm, Endoplasmic Reticulum, and Membrane

Nichols

Blumenfeld

Luebbert

et al. 2022

Preprint

View full text Add to dashboard Cite

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder (MDD). The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist of the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based drug-sensing fluorescent reporters (″iDrugSnFRs″) targeted to the plasma membrane (PM), cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also employed chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER, at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by ≥ 18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for > 2.4 h. They inhibit SERT transport-associated currents 6- or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the ″therapeutic lag″ of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the ″antidepressant discontinuation syndrome″.

show abstract

“…(2) Beta-Adrenergic Receptors . The majority of studies have discovered a predictable pattern of beta-AR downregulation in response to long-term antidepressant or electroconvulsive therapy treatment (ECT) [ 48 , 49 , 50 , 51 ]. In the brain, long-term use of desipramine has been linked to an uncoupling of beta-AR and Gs [ 52 , 51 ].…”

Section: Gpcrs and Mood Disordersmentioning

confidence: 99%

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

Rahman

Islam

Mim

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are intricately involved in the conversion of extracellular feedback to intracellular responses. These specialized receptors possess a crucial role in neurological and psychiatric disorders. Most nonsensory GPCRs are active in almost 90% of complex brain functions. At the time of receptor phosphorylation, a GPCR pathway is essentially activated through a G protein signaling mechanism via a G protein-coupled receptor kinase (GRK). Dopamine, an important neurotransmitter, is primarily involved in the pathophysiology of several CNS disorders; for instance, bipolar disorder, schizophrenia, Parkinson’s disease, and ADHD. Since dopamine, acetylcholine, and glutamate are potent neuropharmacological targets, dopamine itself has potential therapeutic effects in several CNS disorders. GPCRs essentially regulate brain functions by modulating downstream signaling pathways. GPR6, GPR52, and GPR8 are termed orphan GPCRs because they colocalize with dopamine D1 and D2 receptors in neurons of the basal ganglia, either alone or with both receptors. Among the orphan GPCRs, the GPR52 is recognized for being an effective psychiatric receptor. Various antipsychotics like aripiprazole and quetiapine mainly target GPCRs to exert their actions. One of the most important parts of signal transduction is the regulation of G protein signaling (RGS). These substances inhibit the activation of the G protein that initiates GPCR signaling. Developing a combination of RGS inhibitors with GPCR agonists may prove to have promising therapeutic potential. Indeed, several recent studies have suggested that GPCRs represent potentially valuable therapeutic targets for various psychiatric disorders. Molecular biology and genetically modified animal model studies recommend that these enriched GPCRs may also act as potential therapeutic psychoreceptors. Neurotransmitter and neuropeptide GPCR malfunction in the frontal cortex and limbic-related regions, including the hippocampus, hypothalamus, and brainstem, is likely responsible for the complex clinical picture that includes cognitive, perceptual, emotional, and motor symptoms. G protein and GPCR-mediated signaling play a critical role in developing new treatment options for mental health issues, and this study is aimed at offering a thorough picture of that involvement. For patients who are resistant to current therapies, the development of new drugs that target GPCR signaling cascades remains an interesting possibility. These discoveries might serve as a fresh foundation for the creation of creative methods for pharmacologically useful modulation of GPCR function.

show abstract

Antidepressants Produce Persistent Gα_s-Associated Signaling Changes in Lipid Rafts after Drug Withdrawal

Cited by 8 publications

References 68 publications

A novel peripheral biomarker for depression and antidepressant response

A novel peripheral biomarker for depression and antidepressant response

Selective Serotonin Reuptake Inhibitors Within Cells: Temporal Resolution in Cytoplasm, Endoplasmic Reticulum, and Membrane

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

Contact Info

Product

Resources

About

Antidepressants Produce Persistent Gαs-Associated Signaling Changes in Lipid Rafts after Drug Withdrawal

Cited by 8 publications

References 68 publications

A novel peripheral biomarker for depression and antidepressant response

A novel peripheral biomarker for depression and antidepressant response

Selective Serotonin Reuptake Inhibitors Within Cells: Temporal Resolution in Cytoplasm, Endoplasmic Reticulum, and Membrane

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

Contact Info

Product

Resources

About

Antidepressants Produce Persistent Gα_s-Associated Signaling Changes in Lipid Rafts after Drug Withdrawal