TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons
Abstract Thirst plays a vital role in the regulation of body fluid homeostasis and if deregulated can be life-threatening. Interoceptive neurons in the subfornical organ (SFO) are intrinsically osmosensitive and their activation by hyperosmolarity is necessary and sufficient for generating thirst. H...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00628-x |
| _version_ | 1797363704749096960 |
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| author | Guolin Yang Min Jia Guizhou Li Yan-Yu Zang Yang-Yang Chen Yue-Ying Wang Shi-Yu Zhan Shi-Xiao Peng Guoqiang Wan Wei Li Jian-Jun Yang Yun Stone Shi |
| author_facet | Guolin Yang Min Jia Guizhou Li Yan-Yu Zang Yang-Yang Chen Yue-Ying Wang Shi-Yu Zhan Shi-Xiao Peng Guoqiang Wan Wei Li Jian-Jun Yang Yun Stone Shi |
| author_sort | Guolin Yang |
| collection | DOAJ |
| description | Abstract Thirst plays a vital role in the regulation of body fluid homeostasis and if deregulated can be life-threatening. Interoceptive neurons in the subfornical organ (SFO) are intrinsically osmosensitive and their activation by hyperosmolarity is necessary and sufficient for generating thirst. However, the primary molecules sensing systemic osmolarity in these neurons remain elusive. Here we show that the mechanosensitive TMEM63B cation channel is the osmosensor required for the interoceptive neurons to drive thirst. TMEM63B channel is highly expressed in the excitatory SFO thirst neurons. TMEM63B deletion in these neurons impaired hyperosmolarity-induced drinking behavior, while re-expressing TMEM63B in SFO restored water appetite in TMEM63B-deficient mice. Remarkably, hyperosmolarity activates TMEM63B channels, leading to depolarization and increased firing rate of the interoceptive neurons, which drives drinking behavior. Furthermore, TMEM63B deletion did not affect sensitivities of the SFO neurons to angiotensin II or hypoosmolarity, suggesting that TMEM63B plays a specialized role in detecting hyperosmolarity in SFO neurons. Thus, our results reveal a critical osmosensor molecule for the generation of thirst perception. |
| first_indexed | 2024-03-08T16:24:49Z |
| format | Article |
| id | doaj.art-f0ba90d0c37045fc9062e9199aebbddc |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-03-08T16:24:49Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-f0ba90d0c37045fc9062e9199aebbddc2024-01-07T12:10:44ZengNature Publishing GroupCell Discovery2056-59682024-01-0110111510.1038/s41421-023-00628-xTMEM63B channel is the osmosensor required for thirst drive of interoceptive neuronsGuolin Yang0Min Jia1Guizhou Li2Yan-Yu Zang3Yang-Yang Chen4Yue-Ying Wang5Shi-Yu Zhan6Shi-Xiao Peng7Guoqiang Wan8Wei Li9Jian-Jun Yang10Yun Stone Shi11State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurosurgery, Drum Tower Hospital Affiliated to Medical School of Nanjing UniversityDepartment of Anesthesiology, Pain and Perioperative Medicine, First Affiliated Hospital of Zhengzhou UniversityMinistry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Neurosurgery, Drum Tower Hospital Affiliated to Medical School of Nanjing UniversityMinistry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Neurosurgery, Drum Tower Hospital Affiliated to Medical School of Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Neurosurgery, Drum Tower Hospital Affiliated to Medical School of Nanjing UniversityMinistry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing UniversityMinistry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Neurosurgery, Drum Tower Hospital Affiliated to Medical School of Nanjing UniversityDepartment of Anesthesiology, Pain and Perioperative Medicine, First Affiliated Hospital of Zhengzhou UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Neurosurgery, Drum Tower Hospital Affiliated to Medical School of Nanjing UniversityAbstract Thirst plays a vital role in the regulation of body fluid homeostasis and if deregulated can be life-threatening. Interoceptive neurons in the subfornical organ (SFO) are intrinsically osmosensitive and their activation by hyperosmolarity is necessary and sufficient for generating thirst. However, the primary molecules sensing systemic osmolarity in these neurons remain elusive. Here we show that the mechanosensitive TMEM63B cation channel is the osmosensor required for the interoceptive neurons to drive thirst. TMEM63B channel is highly expressed in the excitatory SFO thirst neurons. TMEM63B deletion in these neurons impaired hyperosmolarity-induced drinking behavior, while re-expressing TMEM63B in SFO restored water appetite in TMEM63B-deficient mice. Remarkably, hyperosmolarity activates TMEM63B channels, leading to depolarization and increased firing rate of the interoceptive neurons, which drives drinking behavior. Furthermore, TMEM63B deletion did not affect sensitivities of the SFO neurons to angiotensin II or hypoosmolarity, suggesting that TMEM63B plays a specialized role in detecting hyperosmolarity in SFO neurons. Thus, our results reveal a critical osmosensor molecule for the generation of thirst perception.https://doi.org/10.1038/s41421-023-00628-x |
| spellingShingle | Guolin Yang Min Jia Guizhou Li Yan-Yu Zang Yang-Yang Chen Yue-Ying Wang Shi-Yu Zhan Shi-Xiao Peng Guoqiang Wan Wei Li Jian-Jun Yang Yun Stone Shi TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons Cell Discovery |
| title | TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons |
| title_full | TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons |
| title_fullStr | TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons |
| title_full_unstemmed | TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons |
| title_short | TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons |
| title_sort | tmem63b channel is the osmosensor required for thirst drive of interoceptive neurons |
| url | https://doi.org/10.1038/s41421-023-00628-x |
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