Presynaptic PMCA interacts with Dlg, regulating in vivo synaptic calcium in Drosophila larval NMJ

Dlg organizes presynaptic PMCA into discrete peri-active-zone clusters at the Drosophila melanogaster larval NMJ, and disrupting either increases spontaneous release and asynchronous release after high-frequency stimulation.

• Why it matters: Presynaptic Ca2+ extrusion must be tightly positioned to control neurotransmitter release, but how PMCA nanoscale clustering is regulated in vivo and how it shapes Ca2+ dynamics remained unclear.
• What they did: Using co-immunoprecipitation and super-resolution STED microscopy, the study showed PMCA co-localizes and interacts with Dlg in presynaptic membrane clusters; neuronal DlgS97 depletion and PMCA C-terminal PDZ-binding motif reporter assays tested the mechanism.
• The result: DlgS97 loss redistributed PMCA into smaller puncta without changing abundance, and reducing PMCA or Dlg increased spontaneous release and enhanced asynchronous release, while PMCA depletion prolonged postsynaptic current decay during repetitive stimulation.

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