Regulation of quantal shape by Rab3A: evidence for a fusion pore-dependent mechanism

The function of Rab3A, a small GTPase located on synaptic vesicles, is not well understood. Studies in the Rab3A −/− mouse support a role in activity-dependent plasticity, but have not reported any effects on spontaneously occurring miniature synaptic currents, except that there is a decrease in...

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Bibliographic Details
Published in:The Journal of physiology 2008-08, Vol.586 (16), p.3949-3962
Main Authors: Wang, Xueyong, Thiagarajan, Ramachandran, Wang, Qingbo, Tewolde, Teclemichael, Rich, Mark M., Engisch, Kathrin L.
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Chromaffin Cells - physiology
Excitatory Postsynaptic Potentials - physiology
Ion Channel Gating - physiology
Membrane Fusion - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neuroscience
Porosity
rab3A GTP-Binding Protein - metabolism
Synaptic Transmission - physiology
Synaptic Vesicles - metabolism
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Summary:The function of Rab3A, a small GTPase located on synaptic vesicles, is not well understood. Studies in the Rab3A −/− mouse support a role in activity-dependent plasticity, but have not reported any effects on spontaneously occurring miniature synaptic currents, except that there is a decrease in resting frequency at the neuromuscular junction. Therefore we were surprised to find an increase in the occurrence of mEPCs with abnormally long half-widths at the neuromuscular junctions of Rab3A −/− mice. The abnormal miniature endplate currents (mEPCs), which have significantly greater charge than the average mEPCs for the same fibres, could arise from larger vesicles. However, the type of mEPC most increased in Rab3A −/− mice has a slow rise, which suggests it is not the result of full collapse fusion. To test if the slow mEPCs increased after loss of Rab3A could be due to malfunctioning fusion pores, we used carbon fibre amperometry to record pre-spike feet, which have been shown to correspond to the initial opening of a narrow fusion pore, in adrenal chromaffin cells of wild-type and Rab3A −/− mice. We found that small amplitude pre-spike feet with abnormally long durations were increased in Rab3A −/− cells. The correspondence between mEPC and amperometric data supports our interpretation that slow rising, long half-width mEPCs are caused by reduced diameter fusion pores that remain open longer. These data could be explained by a direct action of Rab3A on the fusion pore, or by Rab3A-dependent control of vesicles with unusual fusion pore characteristics.
ISSN:0022-3751
1469-7793
DOI:10.1113/jphysiol.2008.151191