Clathrin coat controls synaptic vesicle acidification by blocking vacuolar ATpase activity

Zohreh Farsi, Sindhuja Gowrisankaran, Matija Krunic, Burkhard Rammner, Andrew Woehler, Eileen M. Lafer, Carsten Mim, Reinhard Jahn, Ira Milosevic

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Newly-formed synaptic vesicles (SVs) are rapidly acidified by vacuolar adenosine triphosphatases (vATPases), generating a proton electrochemical gradient that drives neurotransmitter loading. Clathrin-mediated endocytosis is needed for the formation of new SVs, yet it is unclear when endocytosed vesicles acidify and refill at the synapse. Here, we isolated clathrin-coated vesicles (CCVs) from mouse brain to measure their acidification directly at the single vesicle level. We observed that the ATP-induced acidification of CCVs was strikingly reduced in comparison to SVs. Remarkably, when the coat was removed from CCVs, uncoated vesicles regained ATP-dependent acidification, demonstrating that CCVs contain the functional vATPase, yet its function is inhibited by the clathrin coat. Considering the known structures of the vATPase and clathrin coat, we propose a model in which the formation of the coat surrounds the vATPase and blocks its activity. Such inhibition is likely fundamental for the proper timing of SV refilling.

Original languageEnglish (US)
Article numbere32569
StatePublished - Apr 13 2018

ASJC Scopus subject areas

  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience


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