Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2

M. Dolores Martín-de-Saavedra, Marc Dos Santos, Lorenza Culotta, Olga Varea, Benjamin P. Spielman, Euan Parnell, Marc P. Forrest, Ruoqi Gao, Sehyoun Yoon, Emmarose McCoig, Hiba A. Jalloul, Kristoffer Myczek, Natalia Khalatyan, Elizabeth A. Hall, Liam S. Turk, Antonio Sanz-Clemente, Davide Comoletti, Stefan F. Lichtenthaler, Jeffrey S. Burgdorf, Maria V. BarbolinaJeffrey N. Savas, Peter Penzes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Although many neuronal membrane proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding (ES). Here, we show that the neuronal sheddome is detectable in human cerebrospinal fluid (hCSF) and is enriched in neurodevelopmental disorder (NDD) risk factors. Among shed synaptic proteins is the ectodomain of CNTNAP2 (CNTNAP2-ecto), a prominent NDD risk factor. CNTNAP2 undergoes activity-dependent ES via MMP9 (matrix metalloprotease 9), and CNTNAP2-ecto levels are reduced in the hCSF of individuals with autism spectrum disorder. Using mass spectrometry, we identified the plasma membrane Ca2+ ATPase (PMCA) extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto enhances the activity of PMCA2 and regulates neuronal network dynamics in a PMCA2-dependent manner. Our data underscore the promise of sheddome analysis in discovering neurobiological mechanisms, provide insight into the biology of ES and its relationship with the CSF, and reveal a mechanism of regulation of Ca2+ homeostasis and neuronal network synchrony by a shed ectodomain.

Original languageEnglish (US)
Pages (from-to)627-643.e9
Issue number4
StatePublished - Feb 16 2022


  • autism
  • bioinformatics
  • calcium
  • cerebrospinal fluid
  • ectodomain shedding
  • network dynamics
  • proteomics
  • schizophrenia
  • sheddome

ASJC Scopus subject areas

  • Neuroscience(all)


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