GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions
Dementia and autoimmune diseases are prevalent conditions with limited treatment options. Taurine and homotaurine (HT) are naturally occurring sulfonate amino acids, with taurine being highly abundant in animal tissues, but declining with age in the blood. HT is a blood-brain barrier permeable drug...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1271203/full |
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| author | Pratap Meera Mikko Uusi-Oukari Gerald S. Lipshutz Gerald S. Lipshutz Gerald S. Lipshutz Gerald S. Lipshutz Martin Wallner |
| author_facet | Pratap Meera Mikko Uusi-Oukari Gerald S. Lipshutz Gerald S. Lipshutz Gerald S. Lipshutz Gerald S. Lipshutz Martin Wallner |
| author_sort | Pratap Meera |
| collection | DOAJ |
| description | Dementia and autoimmune diseases are prevalent conditions with limited treatment options. Taurine and homotaurine (HT) are naturally occurring sulfonate amino acids, with taurine being highly abundant in animal tissues, but declining with age in the blood. HT is a blood-brain barrier permeable drug under investigation for Alzheimer’s disease. HT also has beneficial effects in a mouse model of multiple sclerosis likely through an anti-inflammatory mechanism mediated by GABAA receptor (GABAAR) agonism in immune cells. While both taurine and HT are structural GABA analogs and thought to be GABA mimetics at GABAARs, there is uncertainty concerning their potency as GABA mimetics on native GABAARs. We show that HT is a very potent GABA mimetic, as it evokes GABAAR-mediated currents with an EC50 of 0.4 μM (vs. 3.7 μM for GABA and 116 µM for taurine) in murine cerebellar granule cells in brain slices, with both taurine and HT having similar efficacy in activating native GABAARs. Furthermore, HT displaces the high affinity GABAAR ligand [3H]muscimol at similarly low concentrations (HT IC50 of 0.16 μM vs. 125 μM for taurine) in mouse brain homogenates. The potency of taurine and HT as GABAAR agonists aligns with endogenous concentrations of taurine in the blood and with HT concentrations achieved in the brain following oral administration of HT or the HT pro-drug ALZ-801. Consequently, we discuss that GABAARs subtypes, similar to the ones we studied here in neurons, are plausible targets for mediating the potential beneficial effects of taurine in health and life-span extension and the beneficial HT effects in dementia and autoimmune conditions. |
| first_indexed | 2024-03-08T23:25:08Z |
| format | Article |
| id | doaj.art-bd9b4f178fa4409b835d7e183ca82dd8 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-08T23:25:08Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-bd9b4f178fa4409b835d7e183ca82dd82023-12-14T17:24:07ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-12-011410.3389/fphar.2023.12712031271203GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actionsPratap Meera0Mikko Uusi-Oukari1Gerald S. Lipshutz2Gerald S. Lipshutz3Gerald S. Lipshutz4Gerald S. Lipshutz5Martin Wallner6Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA, United StatesIntegrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, FinlandDepartment of Surgery, University of California, Los Angeles, Los Angeles, CA, United StatesMolecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, United StatesIntellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA, United StatesSemel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Surgery, University of California, Los Angeles, Los Angeles, CA, United StatesDementia and autoimmune diseases are prevalent conditions with limited treatment options. Taurine and homotaurine (HT) are naturally occurring sulfonate amino acids, with taurine being highly abundant in animal tissues, but declining with age in the blood. HT is a blood-brain barrier permeable drug under investigation for Alzheimer’s disease. HT also has beneficial effects in a mouse model of multiple sclerosis likely through an anti-inflammatory mechanism mediated by GABAA receptor (GABAAR) agonism in immune cells. While both taurine and HT are structural GABA analogs and thought to be GABA mimetics at GABAARs, there is uncertainty concerning their potency as GABA mimetics on native GABAARs. We show that HT is a very potent GABA mimetic, as it evokes GABAAR-mediated currents with an EC50 of 0.4 μM (vs. 3.7 μM for GABA and 116 µM for taurine) in murine cerebellar granule cells in brain slices, with both taurine and HT having similar efficacy in activating native GABAARs. Furthermore, HT displaces the high affinity GABAAR ligand [3H]muscimol at similarly low concentrations (HT IC50 of 0.16 μM vs. 125 μM for taurine) in mouse brain homogenates. The potency of taurine and HT as GABAAR agonists aligns with endogenous concentrations of taurine in the blood and with HT concentrations achieved in the brain following oral administration of HT or the HT pro-drug ALZ-801. Consequently, we discuss that GABAARs subtypes, similar to the ones we studied here in neurons, are plausible targets for mediating the potential beneficial effects of taurine in health and life-span extension and the beneficial HT effects in dementia and autoimmune conditions.https://www.frontiersin.org/articles/10.3389/fphar.2023.1271203/fulltaurinehomotaurineinflammationGABAA receptorAlzheimer’s diseaseGABA-mimetics |
| spellingShingle | Pratap Meera Mikko Uusi-Oukari Gerald S. Lipshutz Gerald S. Lipshutz Gerald S. Lipshutz Gerald S. Lipshutz Martin Wallner GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions Frontiers in Pharmacology taurine homotaurine inflammation GABAA receptor Alzheimer’s disease GABA-mimetics |
| title | GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions |
| title_full | GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions |
| title_fullStr | GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions |
| title_full_unstemmed | GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions |
| title_short | GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions |
| title_sort | gabaa receptors as plausible molecular targets and mediators for taurine and homotaurine actions |
| topic | taurine homotaurine inflammation GABAA receptor Alzheimer’s disease GABA-mimetics |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1271203/full |
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