Gαs, adenylyl cyclase, and their relationship to the diagnosis and treatment of depression

Schappi, Jeffrey M.; Rasenick, Mark M.

doi:10.3389/fphar.2022.1012778

Cited by 6 publications

(6 citation statements)

References 103 publications

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“…Ketamine and 2R,6R-HNK are lipophilic and remove G s from the lipid raft. This has a positive effect on the interaction between G S and adenylate cyclase and thus on the production of cAMP, the activation of PKA, and the CREB-target gene BDNF [ 82 , 124 ]. The authors consider it likely that other lipid-soluble anesthetics act similarly to ketamine and 2R,6R-HNK.…”

Section: Discussionmentioning

confidence: 99%

“…to varying extents upregulate heme oxygenase-1 expression [ 218 ]. The ketamine-induced displacement of G S from the lipid rafts occurs much more rapidly than with, for instance, tricyclic antidepressants [ 82 ] and could be an explanation for ketamine’s faster onset of antidepressant activity. It is conceivable that microglial cells are the targets for these effects [ 41 , 229 , 230 ].…”

Section: Discussionmentioning

confidence: 99%

“…AGC-kinases include the protein kinases PKA, PKB/Akt, PKC, PKG, S6K, and others [ 15 , 78 , 79 ]. Data from patients indicate that the cAMP-PKA pathway is hypoactive in MDD [ 80 , 81 , 82 ], so GSK3 is tendentially hyperactive [ 83 ]. This prediction is consistent with observations in MDD patients that both the nuclear translocation of NRF2 and the NRF2-mediated gene transcriptions are diminished [ 84 ], whereas biomarkers reflecting oxidative damage are elevated [ 85 , 86 ].…”

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

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Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles

Kalkman

2023

Biomedicines

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Depression is a major public health concern. Unfortunately, the present antidepressants often are insufficiently effective, whilst the discovery of more effective antidepressants has been extremely sluggish. The objective of this review was to combine the literature on depression with the pharmacology of antidepressant compounds, in order to formulate a conceivable pathophysiological process, allowing proposals how to accelerate the discovery process. Risk factors for depression initiate an infection-like inflammation in the brain that involves activation microglial Toll-like receptors and glycogen synthase kinase-3β (GSK3β). GSK3β activity alters the balance between two competing transcription factors, the pro-inflammatory/pro-oxidative transcription factor NFκB and the neuroprotective, anti-inflammatory and anti-oxidative transcription factor NRF2. The antidepressant activity of tricyclic antidepressants is assumed to involve activation of GS-coupled microglial receptors, raising intracellular cAMP levels and activation of protein kinase A (PKA). PKA and similar kinases inhibit the enzyme activity of GSK3β. Experimental antidepressant principles, including cannabinoid receptor-2 activation, opioid μ receptor agonists, 5HT2 agonists, valproate, ketamine and electrical stimulation of the Vagus nerve, all activate microglial pathways that result in GSK3β-inhibition. An in vitro screen for NRF2-activation in microglial cells with TLR-activated GSK3β activity, might therefore lead to the detection of totally novel antidepressant principles with, hopefully, an improved therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

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Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles

Kalkman

2023

Biomedicines

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“…The heterotrimeric G protein, Gs α-subunit (Gsα) is enriched predominantly in lipid rafts in subjects with a major depressive disorder [ 74 ]. Gsα is normally distributed between non-raft regions where it promotes neurotransmitter-activated adenylyl cyclase activity and lipid raft regions where the adenylyl cyclase activation of Gsα is impaired.…”

Section: Cerebellar Raft-binding Proteinsmentioning

confidence: 99%

The Regulatory Roles of Cerebellar Glycosphingolipid Microdomains/Lipid Rafts

Komatsuya

Kikuchi

Hirabayashi

et al. 2023

IJMS

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Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the regulation of vital cellular processes. Cerebellar lipid rafts are cell surface ganglioside microdomains for the attachment of GPI-anchored neural adhesion molecules and downstream signaling molecules such as Src-family kinases and heterotrimeric G proteins. In this review, we summarize our recent findings on signaling in ganglioside GD3 rafts of cerebellar granule cells and several findings by other groups on the roles of lipid rafts in the cerebellum. TAG-1, of the contactin group of immunoglobulin superfamily cell adhesion molecules, is a phosphacan receptor. Phosphacan regulates the radial migration signaling of cerebellar granule cells, via Src-family kinase Lyn, by binding to TAG-1 on ganglioside GD3 rafts. Chemokine SDF-1α, which induces the tangential migration of cerebellar granule cells, causes heterotrimeric G protein Goα translocation to GD3 rafts. Furthermore, the functional roles of cerebellar raft-binding proteins including cell adhesion molecule L1, heterotrimeric G protein Gsα, and L-type voltage-dependent calcium channels are discussed.

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“…There is post mortem evidence that in subjects with MDD, lipid rafts are enriched in the heterotrimeric G protein, Gas, consistent with diminished cAMP signaling (Targum et al, 2022). Gas stimulates adenylyl cyclase more efficiently when located outside lipid rafts than when it is located within them, and chronic treatment with ketamine facilitates G protein exodus from those rafts (Wray et al, 2019;Schappi and Rasenick, 2022). The complex mechanism of antidepressant action of ketamine has been extensively discussed in many reviews (Kowalczyk et al, 2021;Hess et al, 2022).…”

Section: Mechanism Of Antidepressant Action Of Ketaminementioning

confidence: 99%

Ketamine – A New Antidepressant Drug with Anti-Inflammatory Properties

Jóźwiak-Bębenista,

Sokołowska,

Wiktorowska-Owczarek

et al. 2023

J Pharmacol Exp Ther

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Ketamine is a new, potent and rapid-acting antidepressant approved for therapy of treatment-resistant depression, which has a different mechanism of action than currently-available antidepressant therapies. It owes its uniquely potent antidepressant properties to a complex mechanism of action, which currently remains unclear. However, it is thought that it acts by modulating the functioning of the glutamatergic system, which plays an important role in the process of neuroplasticity associated with depression. However, preclinical and clinical studies have also found ketamine to reduce inflammation, either directly or indirectly (by activating neuroprotective branches of the kynurenine pathway), among patients exhibiting higher levels of inflammation. Inflammation and immune system activation are believed to play key roles in the development and course of depression. Therefore, the present work examines the role of the antidepressant effect of ketamine and its antiinflammatory properties in the treatment of depression. SIGNIFICANCE STATEMENTThe present work examines the relationship between the antidepressant effect of ketamine and its anti-inflammatory properties, and the resulting benefits in treatment-resistant depression (TRD). The antidepressant mechanism of ketamine remains unclear, and there is an urgent need to develop new therapeutic strategies for treatment of depression, particularly TRD.

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Gαs, adenylyl cyclase, and their relationship to the diagnosis and treatment of depression

Cited by 6 publications

References 103 publications

Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles

Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles

The Regulatory Roles of Cerebellar Glycosphingolipid Microdomains/Lipid Rafts

Ketamine – A New Antidepressant Drug with Anti-Inflammatory Properties

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