Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21
Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C...
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MDPI AG
2021-08-01
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| author | Liina Laukkanen Cassiano R. A. F. Diniz Sebastien Foulquier Jos Prickaerts Eero Castrén Plinio C. Casarotto |
| author_facet | Liina Laukkanen Cassiano R. A. F. Diniz Sebastien Foulquier Jos Prickaerts Eero Castrén Plinio C. Casarotto |
| author_sort | Liina Laukkanen |
| collection | DOAJ |
| description | Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1–10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect. |
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| format | Article |
| id | doaj.art-5e6b24cbe89043e590485d050b52c80c |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T08:29:15Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj.art-5e6b24cbe89043e590485d050b52c80c2023-11-22T09:11:37ZengMDPI AGPharmaceuticals1424-82472021-08-0114877310.3390/ph14080773Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21Liina Laukkanen0Cassiano R. A. F. Diniz1Sebastien Foulquier2Jos Prickaerts3Eero Castrén4Plinio C. Casarotto5Neuroscience Center, HiLife, University of Helsinki, 00014 Helsinki, FinlandDepartment of Pharmacology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, SP, BrazilDepartment of Pharmacology and Toxicology, CARIM-School for Cardiovascular Diseases, MHeNS-School for Mental Health and Neuroscience, Maastricht University, 6229 ER Maastricht, The NetherlandsDepartment of Psychiatry and Neuropsychology, MHeNS-School for Mental Health and Neuroscience, Maastricht University, 6229 ER Maastricht, The NetherlandsNeuroscience Center, HiLife, University of Helsinki, 00014 Helsinki, FinlandNeuroscience Center, HiLife, University of Helsinki, 00014 Helsinki, FinlandBlockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1–10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.https://www.mdpi.com/1424-8247/14/8/773compound 21angiotensin 2 type 2 receptor (AT2R)neurotrophin receptor type 2 (NTRK2)renin-angiotensin system (RAS)fear conditioning |
| spellingShingle | Liina Laukkanen Cassiano R. A. F. Diniz Sebastien Foulquier Jos Prickaerts Eero Castrén Plinio C. Casarotto Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21 Pharmaceuticals compound 21 angiotensin 2 type 2 receptor (AT2R) neurotrophin receptor type 2 (NTRK2) renin-angiotensin system (RAS) fear conditioning |
| title | Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21 |
| title_full | Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21 |
| title_fullStr | Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21 |
| title_full_unstemmed | Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21 |
| title_short | Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21 |
| title_sort | facilitation of trkb activation by the angiotensin ii receptor type 2 at2r agonist c21 |
| topic | compound 21 angiotensin 2 type 2 receptor (AT2R) neurotrophin receptor type 2 (NTRK2) renin-angiotensin system (RAS) fear conditioning |
| url | https://www.mdpi.com/1424-8247/14/8/773 |
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