Shed CNTNAP2 Ectodomain is Detectable in CSF and Regulates Ca Homeostasis and Network Synchrony Via PMCA2/ATP2B2

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2021 Dec 18

PMID 34921780

Citations 15

Authors

M Dolores Martin-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 Barbolina

Jeffrey N Savas

Peter Penzes

Affiliations

Soon will be listed here.

Abstract

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 Ca 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 Ca homeostasis and neuronal network synchrony by a shed ectodomain.

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