Neuromodulator release in neurons requires two functionally redundant calcium sensors

Rhodé van Westen, Josse Poppinga, Rocío Díez Arazola, Ruud F. Toonen*, Matthijs Verhage

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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Abstract

Neuropeptides and neurotrophic factors secreted from dense core vesicles (DCVs) control many brain functions, but the calcium sensors that trigger their secretion remain unknown. Here, we show that in mouse hippocampal neurons, DCV fusion is strongly and equally reduced in synaptotagmin-1 (Syt1)- or Syt7-deficient neurons, but combined Syt1/Syt7 deficiency did not reduce fusion further. Cross-rescue, expression of Syt1 in Syt7-deficient neurons, or vice versa, completely restored fusion. Hence, both sensors are rate limiting, operating in a single pathway. Overexpression of either sensor in wild-type neurons confirmed this and increased fusion. Syt1 traveled with DCVs and was present on fusing DCVs, but Syt7 supported fusion largely from other locations. Finally, the duration of single DCV fusion events was reduced in Syt1-deficient but not Syt7-deficient neurons. In conclusion, two functionally redundant calcium sensors drive neuromodulator secretion in an expression-dependent manner. In addition, Syt1 has a unique role in regulating fusion pore duration.

Original languageEnglish
Article numbere2012137118
Pages (from-to)1-12
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number18
Early online date26 Apr 2021
DOIs
Publication statusPublished - 4 May 2021

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Robbert Zalm for cloning and producing viral particles; Frank den Oudsten, Lisa Laan, and Desiree Schut for producing glia and for primary culture assistance; Joke Wortel for animal breeding; Jurjen Broeke for technical assistance; Jurjen Broeke and Alessandro Moro for MATLAB programming; Ingrid Saarloos for protein chemistry; Frank den Oudsten and Joost Hoetjes for genotyping assistance; and members of the Center for Neurogenomics and Cognitive Research DCV project team for fruitful discussions. This work is supported by a European Research Council Advanced Grant (322966) of the European Union (to M.V.).

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • Dense core vesicles
  • Hippocampal neurons
  • Neuromodulators
  • Synaptotagmin-1
  • Synaptotagmin-7

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