Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release
Abstract Neurotransmitters are released from synaptic vesicles with remarkable precision in response to presynaptic calcium influx but exhibit significant heterogeneity in exocytosis timing and efficacy based on the recent history of activity. This heterogeneity is critical for information transfer...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54960-1 |
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| author | Dipayan Bose Manindra Bera Christopher A. Norman Yulia Timofeeva Kirill E. Volynski Shyam S. Krishnakumar |
| author_facet | Dipayan Bose Manindra Bera Christopher A. Norman Yulia Timofeeva Kirill E. Volynski Shyam S. Krishnakumar |
| author_sort | Dipayan Bose |
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| description | Abstract Neurotransmitters are released from synaptic vesicles with remarkable precision in response to presynaptic calcium influx but exhibit significant heterogeneity in exocytosis timing and efficacy based on the recent history of activity. This heterogeneity is critical for information transfer in the brain, yet its molecular basis remains poorly understood. Here, we employ a biochemically-defined fusion assay under physiologically relevant conditions to delineate the minimal protein machinery sufficient to account for various modes of calcium-triggered vesicle fusion dynamics. We find that Synaptotagmin-1, Synaptotagmin-7, and Complexin synergistically restrain SNARE complex assembly, thus preserving vesicles in a stably docked state at rest. Upon calcium activation, Synaptotagmin-1 induces rapid vesicle fusion, while Synaptotagmin-7 mediates delayed fusion. Competitive binding of Synaptotagmin-1 and Synaptotagmin-7 to the same SNAREs, coupled with differential rates of calcium-triggered fusion clamp reversal, govern the overall kinetics of vesicular fusion. Under conditions mimicking sustained neuronal activity, the Synaptotagmin-7 fusion clamp is destabilized by the elevated basal calcium concentration, thereby enhancing the synchronous component of fusion. These findings provide a direct demonstration that a small set of proteins is sufficient to account for how nerve terminals adapt and regulate the calcium-evoked neurotransmitter exocytosis process to support their specialized functions in the nervous system. |
| format | Article |
| id | doaj-art-f4586f498dac4ec0a766f4a3ac555d08 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-f4586f498dac4ec0a766f4a3ac555d082025-01-05T12:34:48ZengNature PortfolioNature Communications2041-17232024-12-0115111110.1038/s41467-024-54960-1Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter releaseDipayan Bose0Manindra Bera1Christopher A. Norman2Yulia Timofeeva3Kirill E. Volynski4Shyam S. Krishnakumar5Nanobiology Institute, Yale UniversityNanobiology Institute, Yale UniversityDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of NeurologyDepartment of Computer Science, University of WarwickDepartment of Cell Biology, School of Medicine, Yale UniversityNanobiology Institute, Yale UniversityAbstract Neurotransmitters are released from synaptic vesicles with remarkable precision in response to presynaptic calcium influx but exhibit significant heterogeneity in exocytosis timing and efficacy based on the recent history of activity. This heterogeneity is critical for information transfer in the brain, yet its molecular basis remains poorly understood. Here, we employ a biochemically-defined fusion assay under physiologically relevant conditions to delineate the minimal protein machinery sufficient to account for various modes of calcium-triggered vesicle fusion dynamics. We find that Synaptotagmin-1, Synaptotagmin-7, and Complexin synergistically restrain SNARE complex assembly, thus preserving vesicles in a stably docked state at rest. Upon calcium activation, Synaptotagmin-1 induces rapid vesicle fusion, while Synaptotagmin-7 mediates delayed fusion. Competitive binding of Synaptotagmin-1 and Synaptotagmin-7 to the same SNAREs, coupled with differential rates of calcium-triggered fusion clamp reversal, govern the overall kinetics of vesicular fusion. Under conditions mimicking sustained neuronal activity, the Synaptotagmin-7 fusion clamp is destabilized by the elevated basal calcium concentration, thereby enhancing the synchronous component of fusion. These findings provide a direct demonstration that a small set of proteins is sufficient to account for how nerve terminals adapt and regulate the calcium-evoked neurotransmitter exocytosis process to support their specialized functions in the nervous system.https://doi.org/10.1038/s41467-024-54960-1 |
| spellingShingle | Dipayan Bose Manindra Bera Christopher A. Norman Yulia Timofeeva Kirill E. Volynski Shyam S. Krishnakumar Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release Nature Communications |
| title | Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release |
| title_full | Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release |
| title_fullStr | Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release |
| title_full_unstemmed | Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release |
| title_short | Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release |
| title_sort | minimal presynaptic protein machinery governing diverse kinetics of calcium evoked neurotransmitter release |
| url | https://doi.org/10.1038/s41467-024-54960-1 |
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