Flower/FLWR-1 regulates neuronal activity via the plasma membrane Ca2+ ATPase to promote recycling of synaptic vesicles
The Flower protein was suggested to couple the fusion of synaptic vesicles (SVs) to their recycling in different model organisms. It is supposed to trigger activity-dependent bulk endocytosis by conducting Ca2+ at endocytic sites. However, this mode of action is debated. Here, we investigated the ro...
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eLife Sciences Publications Ltd
2025-05-01
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| Online Access: | https://elifesciences.org/articles/103870 |
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| author | Marius Seidenthal Jasmina Redzovic Jana F Liewald Dennis Rentsch Stepan Shapiguzov Noah Schuh Nils Rosenkranz Stefan Eimer Alexander Gottschalk |
| author_facet | Marius Seidenthal Jasmina Redzovic Jana F Liewald Dennis Rentsch Stepan Shapiguzov Noah Schuh Nils Rosenkranz Stefan Eimer Alexander Gottschalk |
| author_sort | Marius Seidenthal |
| collection | DOAJ |
| description | The Flower protein was suggested to couple the fusion of synaptic vesicles (SVs) to their recycling in different model organisms. It is supposed to trigger activity-dependent bulk endocytosis by conducting Ca2+ at endocytic sites. However, this mode of action is debated. Here, we investigated the role of the Caenorhabditis elegans homologue FLWR-1 in neurotransmission. Our results confirm that FLWR-1 facilitates the recycling of SVs at the neuromuscular junction (NMJ). Ultrastructural analysis of synaptic boutons after hyperstimulation revealed an accumulation of large endocytic structures in flwr-1 mutants. These findings do not support a role of FLWR-1 in the formation of bulk endosomes but rather a function in their breakdown. Unexpectedly, the loss of FLWR-1 led to increased neuronal Ca2+ levels in axon terminals during stimulation, particularly in GABAergic motor neurons, causing excitation-inhibition imbalance. We found that this increased NMJ transmission might be caused by deregulation of MCA-3, the nematode orthologue of the plasma membrane Ca2+ ATPase (PMCA). In vivo molecular interactions indicated that FLWR-1 may be a positive regulator of the PMCA and might influence its recycling through modification of plasma membrane levels of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). |
| format | Article |
| id | doaj-art-221eac93eeb04eafa4e90d6f88eb82fa |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-221eac93eeb04eafa4e90d6f88eb82fa2025-08-20T03:08:12ZengeLife Sciences Publications LtdeLife2050-084X2025-05-011310.7554/eLife.103870Flower/FLWR-1 regulates neuronal activity via the plasma membrane Ca2+ ATPase to promote recycling of synaptic vesiclesMarius Seidenthal0https://orcid.org/0009-0001-0563-7719Jasmina Redzovic1Jana F Liewald2https://orcid.org/0000-0002-2050-0745Dennis Rentsch3https://orcid.org/0009-0006-9090-9016Stepan Shapiguzov4Noah Schuh5https://orcid.org/0009-0000-1888-7998Nils Rosenkranz6Stefan Eimer7Alexander Gottschalk8https://orcid.org/0000-0002-1197-6119Buchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany; Institute for Biophysical Chemistry, Department of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany; Institute for Biophysical Chemistry, Department of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt, Germany; Institute of Cell Biology and Neuroscience, Goethe-University, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany; Institute for Biophysical Chemistry, Department of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany; Institute for Biophysical Chemistry, Department of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany; Institute for Biophysical Chemistry, Department of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany; Institute for Biophysical Chemistry, Department of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany; Institute for Biophysical Chemistry, Department of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt, GermanyInstitute of Cell Biology and Neuroscience, Goethe-University, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany; Institute for Biophysical Chemistry, Department of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt, GermanyThe Flower protein was suggested to couple the fusion of synaptic vesicles (SVs) to their recycling in different model organisms. It is supposed to trigger activity-dependent bulk endocytosis by conducting Ca2+ at endocytic sites. However, this mode of action is debated. Here, we investigated the role of the Caenorhabditis elegans homologue FLWR-1 in neurotransmission. Our results confirm that FLWR-1 facilitates the recycling of SVs at the neuromuscular junction (NMJ). Ultrastructural analysis of synaptic boutons after hyperstimulation revealed an accumulation of large endocytic structures in flwr-1 mutants. These findings do not support a role of FLWR-1 in the formation of bulk endosomes but rather a function in their breakdown. Unexpectedly, the loss of FLWR-1 led to increased neuronal Ca2+ levels in axon terminals during stimulation, particularly in GABAergic motor neurons, causing excitation-inhibition imbalance. We found that this increased NMJ transmission might be caused by deregulation of MCA-3, the nematode orthologue of the plasma membrane Ca2+ ATPase (PMCA). In vivo molecular interactions indicated that FLWR-1 may be a positive regulator of the PMCA and might influence its recycling through modification of plasma membrane levels of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2).https://elifesciences.org/articles/103870plasma membran Ca2+ ATPasesynaptic vesicle recyclingCa2+ homeostasisPIP2endocytosis |
| spellingShingle | Marius Seidenthal Jasmina Redzovic Jana F Liewald Dennis Rentsch Stepan Shapiguzov Noah Schuh Nils Rosenkranz Stefan Eimer Alexander Gottschalk Flower/FLWR-1 regulates neuronal activity via the plasma membrane Ca2+ ATPase to promote recycling of synaptic vesicles eLife plasma membran Ca2+ ATPase synaptic vesicle recycling Ca2+ homeostasis PIP2 endocytosis |
| title | Flower/FLWR-1 regulates neuronal activity via the plasma membrane Ca2+ ATPase to promote recycling of synaptic vesicles |
| title_full | Flower/FLWR-1 regulates neuronal activity via the plasma membrane Ca2+ ATPase to promote recycling of synaptic vesicles |
| title_fullStr | Flower/FLWR-1 regulates neuronal activity via the plasma membrane Ca2+ ATPase to promote recycling of synaptic vesicles |
| title_full_unstemmed | Flower/FLWR-1 regulates neuronal activity via the plasma membrane Ca2+ ATPase to promote recycling of synaptic vesicles |
| title_short | Flower/FLWR-1 regulates neuronal activity via the plasma membrane Ca2+ ATPase to promote recycling of synaptic vesicles |
| title_sort | flower flwr 1 regulates neuronal activity via the plasma membrane ca2 atpase to promote recycling of synaptic vesicles |
| topic | plasma membran Ca2+ ATPase synaptic vesicle recycling Ca2+ homeostasis PIP2 endocytosis |
| url | https://elifesciences.org/articles/103870 |
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