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J. Biol. Chem., Vol. 278, Issue 42, 41099-41108, October 17, 2003

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Presynaptic N-type Calcium Channels Regulate Synaptic Growth^*

Gabrielle E. Rieckhof, Motojiro Yoshihara, Zhuo Guan and J. Troy Littleton 

From the Picower Center for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Voltage-gated calcium channels couple changes in membrane potential to neuronal functions regulated by calcium, including neurotransmitter release. Here we report that presynaptic N-type calcium channels not only control neurotransmitter release but also regulate synaptic growth at Drosophila neuromuscular junctions. In a screen for behavioral mutants that disrupt synaptic transmission, an allele of the N-type calcium channel locus (Dmca1A) was identified that caused synaptic undergrowth. The underlying molecular defect was identified as a neutralization of a charged residue in the third S4 voltage sensor. RNA interference reduction of N-type calcium channel expression also reduced synaptic growth. Hypomorphic mutations in syntaxin-1A or n-synaptobrevin, which also disrupt neurotransmitter release, did not affect synapse proliferation at the neuromuscular junction, suggesting calcium entry through presynaptic N-type calcium channels, not neurotransmitter release per se, is important for synaptic growth. The reduced synapse proliferation in Dmca1A mutants is not due to increased synapse retraction but instead reflects a role for calcium influx in synaptic growth mechanisms. These results suggest N-type channels participate in synaptic growth through signaling pathways that are distinct from those that mediate neurotransmitter release. Linking presynaptic voltage-gated calcium entry to downstream calcium-sensitive synaptic growth regulators provides an efficient activity-dependent mechanism for modifying synaptic strength.

Received for publication, June 17, 2003 , and in revised form, July 21, 2003.

^* This work was supported by grants from the National Institutes of Health, the Human Frontiers Science Program Organization, and the Searle Scholars Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Alfred P. Sloan Research Fellow. To whom correspondence should be addressed: Picower Center for Learning and Memory, Massachusetts Institute of Technology, E18-672, 50 Ames St., Cambridge, MA 02139. Tel.: 617-452-2605; Fax: 617-452-2249. E-mail: troy{at}mit.edu.

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