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The Journal of Neuroscience, April 2, 2008, 28(14):3668-3682; doi:10.1523/JNEUROSCI.5553-07.2008

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Cellular/Molecular
Presynaptic Calcium Channel Localization and Calcium-Dependent Synaptic Vesicle Exocytosis Regulated by the Fuseless Protein

A. Ashleigh Long,¹ Eunju Kim,² Hung-Tat Leung,² Elvin Woodruff, III,¹ Lingling An,³ R. W. Doerge,³ William L. Pak,² and Kendal Broadie¹

¹Department of Biological Sciences, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37235-1634, and ²Departments of Biological Sciences and ³Statistics, Purdue University, West Lafayette, Indiana 47907

Correspondence should be addressed to Prof. Kendal Broadie, Department of Biological Sciences, Vanderbilt University, VU Station B, Box 351634, Nashville, TN 37235-1634. Email: kendal.broadie{at}vanderbilt.edu

A systematic forward genetic Drosophila screen for electroretinogram mutants lacking synaptic transients identified the fuseless (fusl) gene, which encodes a predicted eight-pass transmembrane protein in the presynaptic membrane. Null fusl mutants display >75% reduction in evoked synaptic transmission but, conversely, an approximately threefold increase in the frequency and amplitude of spontaneous synaptic vesicle fusion events. These neurotransmission defects are rescued by a wild-type fusl transgene targeted only to the presynaptic cell, demonstrating a strictly presynaptic requirement for Fusl function. Defects in FM dye turnover at the synapse show a severely impaired exo-endo synaptic vesicle cycling pool. Consistently, ultrastructural analyses reveal accumulated vesicles arrested in clustered and docked pools at presynaptic active zones. In the absence of Fusl, calcium-dependent neurotransmitter release is dramatically compromised and there is little enhancement of synaptic efficacy with elevated external Ca²⁺ concentrations. These defects are causally linked with severe loss of the Cacophony voltage-gated Ca²⁺ channels, which fail to localize normally at presynaptic active zone domains in the absence of Fusl. These data indicate that Fusl regulates assembly of the presynaptic active zone Ca²⁺ channel domains required for efficient coupling of the Ca²⁺ influx and synaptic vesicle exocytosis during neurotransmission.

Key words: Drosophila; photoreceptor; synapse; synaptic vesicle; exocytosis; neuromuscular junction

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Received Dec. 15, 2007; revised Feb. 29, 2008; accepted March 1, 2008.

Correspondence should be addressed to Prof. Kendal Broadie, Department of Biological Sciences, Vanderbilt University, VU Station B, Box 351634, Nashville, TN 37235-1634. Email: kendal.broadie{at}vanderbilt.edu

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