CNTNAP2 ectodomain, detected in neuronal and CSF sheddomes, modulates Ca2+ dynamics and network synchrony

M. Dolores Martin-de-Saavedra, Marc dos Santos, Olga Varea, Benjamin P. Spielman, Ruoqi Gao, Marc Forrest, Kristoffer Myczek, Natalia Khalatyan, Elizabeth A. Hall, Antonio Sanz-Clemente, Davide Comoletti, Stefan F. Lichtenthaler, Jeffrey N. Savas, Peter Penzes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

While many neuronal membrane-anchored proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding. Using mass spectrometry (MS)-based proteomics, we showed that the neuronal sheddome mirrors human cerebrospinal fluid (hCSF). Among shed synaptic proteins in hCSF was the ectodomain of CNTNAP2 (CNTNAP2-ecto), a risk factor for neurodevelopmental disorders (NDD). Using structured-illumination microscopy (SIM), we mapped the spatial organization of neuronal CNTNAP2-ecto shedding. Using affinity chromatography followed by MS, we identified the ATP2B/PMCA Ca2+ extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto coimmunoprecipitates with PMCA2, a known autism risk factor, and enhances its activity, thereby modulating neuronal Ca2+ levels. Finally, we showed that CNTNAP2-ecto regulates neuronal network synchrony in primary cultures and brain slices. These data provide new insights into the biology of synaptic ectodomain shedding and reveal a novel mechanism of regulation of Ca2+ homeostasis and neuronal network synchrony.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Apr 10 2019

Keywords

  • autism
  • bioinformatics
  • calcium
  • mass spectrometry
  • neural synchrony
  • plasticity
  • proteomics
  • schizophrenia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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