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The Journal of Neuroscience, March 2, 2005, 25(9):2204-2214; doi:10.1523/JNEUROSCI.3610-04.2005

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Cellular/Molecular
The Multiple Functions of Cysteine-String Protein Analyzed at Drosophila Nerve Terminals

Peter Bronk,⁵ Zhiping Nie,⁵ Markus K. Klose,^3,4 Ken Dawson-Scully,³ Jinhui Zhang,¹ R. Meldrum Robertson,⁴ Harold L. Atwood,³ and Konrad E. Zinsmaier^1,2,5

¹Arizona Research Laboratories Division of Neurobiology and ²Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721, ³Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, ⁴Department of Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada, and ⁵Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6974

The synaptic vesicle-associated cysteine-string protein (CSP) is important for synaptic transmission. Previous studies revealed multiple defects at neuromuscular junctions (NMJs) of csp null-mutant Drosophila, but whether these defects are independent of each other or mechanistically linked through J domain mediated-interactions with heat-shock cognate protein 70 (Hsc70) has not been established. To resolve this issue, we genetically dissected the individual functions of CSP by an in vivo structure/function analysis. Expression of mutant CSP lacking the J domain at csp null-mutant NMJs fully restored normal thermo-tolerance of evoked transmitter release but did not completely restore evoked release at room temperature and failed to reverse the abnormal intraterminal Ca²⁺ levels. This suggests that J domain-mediated functions are essential for the regulation of intraterminal Ca²⁺ levels but only partially required for regulating evoked release and not required for protecting evoked release against thermal stress. Hence, CSP can also act as an Hsc70-independent chaperone protecting evoked release from thermal stress. Expression of mutant CSP lacking the L domain restored neurotransmission and partially reversed the abnormal intraterminal Ca²⁺ levels, suggesting that the L domain is important, although not essential, for the role of CSP in regulating intraterminal Ca²⁺ levels. We detected no effects of csp mutations on individual presynaptic Ca²⁺ signals triggered by action potentials, suggesting that presynaptic Ca²⁺ entry is not primarily impaired. Both the J and L domains were also required for the role of CSP in synaptic growth. Together, these results suggest that CSP has several independent synaptic functions, affecting synaptic growth, evoked release, thermal protection of evoked release, and intraterminal Ca²⁺ levels at rest and during stimulation.

Key words: neurosecretion; synapse; calcium; homeostasis; chaperone; vesicle fusion; synaptic plasticity

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Received Sep 1, 2004; revised January 12, 2005; accepted January 13, 2005.

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