TY - JOUR T1 - CNTNAP2 ectodomain, detected in neuronal and CSF sheddomes, modulates Ca<sup>2+</sup> dynamics and network synchrony JF - bioRxiv DO - 10.1101/605378 SP - 605378 AU - M. Dolores Martin-de-Saavedra AU - Marc dos Santos AU - Olga Varea AU - Benjamin P. Spielman AU - Ruoqi Gao AU - Marc Forrest AU - Kristoffer Myczek AU - Natalia Khalatyan AU - Elizabeth A. Hall AU - Antonio Sanz-Clemente AU - Davide Comoletti AU - Stefan F. Lichtenthaler AU - Jeffrey N. Savas AU - Peter Penzes Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/04/10/605378.abstract N2 - 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. ER -