Improved cognitive performance in trace amine-associated receptor 5 (TAAR5) knock-out mice

Maggi, Silvia; Bon, Carlotta; Gustincich, Stefano; Tucci, Valter; Gainetdinov, Raul R.; Espinoza, Stefano

doi:10.1038/s41598-022-18924-z

Cited by 5 publications

(4 citation statements)

References 43 publications

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“…After the dimerization of TAAR1 with the dopamine receptor D2R, dopamine signaling activity shifts from the β-arrestin-2 signaling pathway to Gi activation [ 1 , 55 , 56 , 57 , 58 ]. The study of TAAR5-KO animals and TAAR5 agonist α-NETA also demonstrated effects of TAAR5 absence on dopaminergic transmission functioning, at least in the central nervous system [ 59 , 60 , 61 , 62 , 63 ]. In contrast, the role of TAAR9 in dopaminergic transmission was not described.…”

Section: Discussionmentioning

confidence: 99%

Gut Microbiota Alterations in Trace Amine-Associated Receptor 9 (TAAR9) Knockout Rats

et al. 2022

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Trace amine-associated receptors (TAAR1-TAAR9) are a family of G-protein-coupled monoaminergic receptors which might have great pharmacological potential. It has now been well established that TAAR1 plays an important role in the central nervous system. Interestingly, deletion of TAAR9 in rats leads to alterations in the periphery. Previously, we found that knockout of TAAR9 in rats (TAAR9-KO rats) decreased low-density lipoprotein cholesterol levels in the blood. TAAR9 was also identified in intestinal tissues, and it is known that it responds to polyamines. To elucidate the role of TAAR9 in the intestinal epithelium, we analyzed TAAR9-co-expressed gene clusters in public data for cecum samples. As identified by gene ontology enrichment analysis, in the intestine, TAAR9 is co-expressed with genes involved in intestinal mucosa homeostasis and function, including cell organization, differentiation, and death. Additionally, TAAR9 was co-expressed with genes implicated in dopamine signaling, which may suggest a role for this receptor in the regulation of peripheral dopaminergic transmission. To further investigate how TAAR9 might be involved in colonic mucosal homeostasis, we analyzed the fecal microbiome composition in TAAR9-KO rats and their wild-type littermates. We identified a significant difference in the number of observed taxa between the microbiome of TAAR9-KO and wild-type rats. In TAAR9-KO rats, the gut microbial community became more variable compared with the wild-type rats. Furthermore, it was found that the family Saccharimonadaceae, which is one of the top 10 most abundant families in TAAR9-KO rat feces, is almost completely absent in wild-type animal fecal samples. Taken together, these data indicate a role of TAAR9 in intestinal function.

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Section: Discussionmentioning

confidence: 99%

Gut Microbiota Alterations in Trace Amine-Associated Receptor 9 (TAAR9) Knockout Rats

et al. 2022

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“…This relationship is confirmed by the altered cognitive profile of TAAR5-KO. TAAR5-KO mice showed fewer errors, better execution speed, and higher learning progress [ 113 ].…”

Section: The Family Of Taars—a New Target For Depression Therapy?mentioning

confidence: 99%

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

Shemiakova,

Efimova,

Gainetdinov

2024

Biomedicines

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Depression is a common mental illness of great concern. Current therapy for depression is only suitable for 80% of patients and is often associated with unwanted side effects. In this regard, the search for and development of new antidepressant agents remains an urgent task. In this review, we discuss the current available evidence indicating that G protein-coupled trace amine-associated receptors (TAARs) might represent new targets for depression treatment. The most frequently studied receptor TAAR1 has already been investigated in the treatment of schizophrenia, demonstrating antidepressant and anxiolytic properties. In fact, the TAAR1 agonist Ulotaront is currently undergoing phase 2/3 clinical trials testing its safety and efficacy in the treatment of major depressive disorder and generalized anxiety disorder. Other members of the TAAR family (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) are not only involved in the innate olfaction of volatile amines, but are also expressed in the limbic brain areas. Furthermore, animal studies have shown that TAAR2 and TAAR5 regulate emotional behaviors and thus may hold promise as potential antidepressant targets. Of particular interest is their connection with the dopamine and serotonin systems of the brain and their involvement in the regulation of adult neurogenesis, known to be affected by the antidepressant drugs currently in use. Further non-clinical and clinical studies are necessary to validate TAAR1 (and potentially other TAARs) as novel therapeutic targets for the treatment of depression.

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“…Notably, recent studies found that mTAAR5 is expressed in the major limbic brain areas and is involved in the regulation of emotional behavior, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. 13,17,29,30 Moreover, a correlation between mTAAR5 with adult neurogenesis and dopamine transmission, and its involvement in sensorimotor functions and cognitive processes have been suggested. 17,29−31 The limited knowledge of the druglike ligand space of TAAR5 modulators impairs potential TAAR5-targeted drug discovery campaigns.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Murine subtypes are the best characterized among mammals in terms of the number of ligands. ,− For the mouse TAAR5 (mTAAR5), both agonists (that is trimethylamine, a sexually dimorphic mouse odor secreted into urine, ,, and alpha-NETA, an acetylcholine esterase inhibitor) and antagonists (two 5-HT 1A ligands) are known. Notably, recent studies found that mTAAR5 is expressed in the major limbic brain areas and is involved in the regulation of emotional behavior, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. ,,, Moreover, a correlation between mTAAR5 with adult neurogenesis and dopamine transmission, and its involvement in sensorimotor functions and cognitive processes have been suggested. ,− The limited knowledge of the druglike ligand space of TAAR5 modulators impairs potential TAAR5-targeted drug discovery campaigns. Thus, the discovery of additional ligands is a crucial step in gaining a mechanistic and physiological understanding of TAAR5.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of Mouse Trace Amine-Associated Receptor 5 Antagonists

Nicoli,

Weber,

Bon

et al. 2023

J. Chem. Inf. Model.

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Trace amine-associated receptors (TAARs) were discovered in 2001 as new members of class A G protein-coupled receptors (GPCRs). With the only exception of TAAR1, TAAR members (TAAR2–9, also known as noncanonical olfactory receptors) were originally described exclusively in the olfactory epithelium and believed to mediate the innate perception of volatile amines. However, most noncanonical olfactory receptors are still orphan receptors. Given its recently discovered nonolfactory expression and therapeutic potential, TAAR5 has been the focus of deorphanization campaigns that led to the discovery of a few druglike antagonists. Here, we report four novel TAAR5 antagonists identified through high-throughput screening, which, along with the four ligands published in the literature, constituted our starting point to design a computational strategy for the identification of TAAR5 ligands. We developed a structure-based virtual screening protocol that allowed us to identify three new TAAR5 antagonists with a hit rate of 10%. Despite lacking an experimental structure, we accurately modeled the TAAR5 binding site by integrating comparative sequence- and structure-based analyses of serotonin receptors with homology modeling and side-chain optimization. In summary, we have identified seven new TAAR5 antagonists that could serve as lead candidates for the development of new treatments for depression, anxiety, and neurodegenerative diseases.

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Improved cognitive performance in trace amine-associated receptor 5 (TAAR5) knock-out mice

Cited by 5 publications

References 43 publications

Gut Microbiota Alterations in Trace Amine-Associated Receptor 9 (TAAR9) Knockout Rats

Gut Microbiota Alterations in Trace Amine-Associated Receptor 9 (TAAR9) Knockout Rats

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

Structure-Based Discovery of Mouse Trace Amine-Associated Receptor 5 Antagonists

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