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

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 Ca²⁺ ATPase (PMCA) extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto enhances the activity of PMCA2 and regulates neuron

SUBMITTER: Martin-de-Saavedra MD 

PROVIDER: S-EPMC8857041 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature