Autor: |
Tse LH; Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China., Cheung ST; Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China., Lee S; Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China., Wong YH; Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China.; State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, China.; Hong Kong Center for Neurodegenerative Diseases, 17 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong, China. |
Jazyk: |
angličtina |
Zdroj: |
International journal of molecular sciences [Int J Mol Sci] 2024 Mar 02; Vol. 25 (5). Date of Electronic Publication: 2024 Mar 02. |
DOI: |
10.3390/ijms25052919 |
Abstrakt: |
Melatonin is a neuroendocrine hormone that regulates the circadian rhythm and many other physiological processes. Its functions are primarily exerted through two subtypes of human melatonin receptors, termed melatonin type-1 (MT 1 ) and type-2 (MT 2 ) receptors. Both MT 1 and MT 2 receptors are generally classified as G i -coupled receptors owing to their well-recognized ability to inhibit cAMP accumulation in cells. However, it remains an enigma as to why melatonin stimulates cAMP production in a number of cell types that express the MT 1 receptor. To address if MT 1 can dually couple to G s and G i proteins, we employed a highly sensitive luminescent biosensor (GloSensor TM ) to monitor the real-time changes in the intracellular cAMP level in intact live HEK293 cells that express MT 1 and/or MT 2 . Our results demonstrate that the activation of MT 1 , but not MT 2 , leads to a robust enhancement on the forskolin-stimulated cAMP formation. In contrast, the activation of either MT 1 or MT 2 inhibited cAMP synthesis driven by the activation of the G s -coupled β 2 -adrenergic receptor, which is consistent with a typical G i -mediated response. The co-expression of MT 1 with G s enabled melatonin itself to stimulate cAMP production, indicating a productive coupling between MT 1 and G s . The possible existence of a MT 1 -G s complex was supported through molecular modeling as the predicted complex exhibited structural and thermodynamic characteristics that are comparable to that of MT 1 -G i . Taken together, our data reveal that MT 1 , but not MT 2 , can dually couple to G s and G i proteins, thereby enabling the bi-directional regulation of adenylyl cyclase to differentially modulate cAMP levels in cells that express different complements of MT 1 , MT 2 , and G proteins. |
Databáze: |
MEDLINE |
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