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The Journal of Neuroscience, August 15, 2000, 20(16):6039-6047

Cysteine-String Protein Increases the Calcium Sensitivity of Neurotransmitter Exocytosis in Drosophila

Ken Dawson-Scully², Peter Bronk¹, Harold L. Atwood², and Konrad E. Zinsmaier¹

¹ Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6974, and ² Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Previous studies suggest that the vesicular cysteine-string protein (CSP) may modulate presynaptic Ca²⁺ channel activity in fast neurotransmitter release. To test this hypothesis, we analyzed the dynamics of presynaptic Ca²⁺ ion influx with the Ca²⁺ indicator fluo-4 AM at csp mutant neuromuscular junctions of Drosophila. From 24 to 30°C, stimulus-evoked, relative presynaptic Ca²⁺ signals were increasingly larger in csp mutant boutons than in controls. Above 30°C, Ca²⁺ signals declined and were similar to controls at 34°C. A prolonged decay of Ca²⁺ signals in mutant boutons at high temperatures indicated abnormally slow Ca²⁺ clearance. Cytosolic Ca²⁺ at rest was determined with the ratiometric Ca²⁺ indicator fura-2 AM and was similar in mutant and control boutons at 24°C but higher in mutant boutons at 34°C. Despite larger Ca²⁺ signals in mutant boutons, evoked neurotransmitter release was always reduced in csp mutants and exhibited pronounced facilitation. Thus, a lack of Ca²⁺ entry cannot explain the reduction of neurotransmitter release in csp mutants. At all temperatures tested, raising extracellular Ca²⁺ increased transmitter release elicited by single stimuli in csp mutants. Collectively, these data suggest multiple functions for CSP at synaptic terminals. Increased Ca²⁺ signals coupled with reduced release suggest a direct function of CSP in exocytosis downstream from Ca²⁺ entry. Because the reduction of evoked release in csp mutants is counteracted by increased Ca²⁺ levels, we suggest that CSP primarily increases the Ca²⁺ sensitivity of the exocytotic machinery.

Key words: cysteine-string protein; Ca²⁺ channel; syntaxin; neurotransmitter release; exocytosis; synaptic transmission; Ca²⁺ clearance; Drosophila; neuromuscular junction; Ca²⁺ measurement

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20166039-09$05.00/0

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