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Rabconnectin3α promotes stable activity of the H+ pump on synaptic vesicles in hair cells.

Acidification of synaptic vesicles relies on the vacuolar-type ATPase (V-ATPase) and provides the electrochemical driving force for neurotransmitter exchange. The regulatory mechanisms that ensure assembly of the V-ATPase holoenzyme on synaptic vesicles are unknown. Rabconnectin3α (Rbc3α) is a potential candidate for regulation of V-ATPase activity because of its association with synaptic vesicles and its requirement for acidification of intracellular compartments. Here, we provide the first evidence for a role of Rbc3α in synaptic vesicle acidification and neurotransmission. In this study, we characterized mutant alleles of rbc3α isolated from a large-scale screen for zebrafish with auditory/vestibular defects. We show that Rbc3α is localized to basal regions of hair cells in which synaptic vesicles are present. To determine whether Rbc3α regulates V-ATPase activity, we examined the acidification of synaptic vesicles and localization of the V-ATPase in hair cells. In contrast to wild-type hair cells, we observed that synaptic vesicles had elevated pH, and a cytosolic subunit of the V-ATPase was no longer enriched in synaptic regions of mutant hair cells. As a consequence of defective acidification of synaptic vesicles, afferent neurons in rbc3α mutants had reduced firing rates and reduced accuracy of phase-locked action potentials in response to mechanical stimulation of hair cells. Collectively, our data suggest that Rbc3α modulates synaptic transmission in hair cells by promoting V-ATPase activity in synaptic vesicles.

Pubmed ID: 22875945

Authors

  • Einhorn Z
  • Trapani JG
  • Liu Q
  • Nicolson T

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

August 8, 2012

Associated Grants

  • Agency: NIDCD NIH HHS, Id: R01 DC006880
  • Agency: NIDCD NIH HHS, Id: R01 DC006880
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Acoustic Stimulation
  • Action Potentials
  • Adaptor Proteins, Signal Transducing
  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Enzyme Inhibitors
  • Escape Reaction
  • Green Fluorescent Proteins
  • Hair Cells, Auditory
  • Larva
  • Lateral Line System
  • Macrolides
  • Membrane Transport Proteins
  • Microscopy, Confocal
  • Molecular Biology
  • Mutation
  • Physical Stimulation
  • Proton Pumps
  • RNA, Messenger
  • Sensation Disorders
  • Synaptic Vesicles
  • Vacuolar Proton-Translocating ATPases
  • Video Recording
  • Vision Disorders
  • Zebrafish
  • Zebrafish Proteins