title: Presynaptic N-type calcium channels regulate synaptic growth.
abstract: 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.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Gabrielle E
authors.initials: GE
authors.lastname: Rieckhof
authors.forename: Motojiro
authors.initials: M
authors.lastname: Yoshihara
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Guan
authors.forename: J Troy
authors.initials: JT
authors.lastname: Littleton
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004330:Drosophila; D029721:Drosophila Proteins; D004594:Electrophysiology; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D013696:Temperature; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D029721:Drosophila Proteins; D012330:RNA, Double-Stranded; C472405:cac protein, Drosophila; D004247:DNA; D002118:Calcium