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Activity-dependent cleavage of dyskinesia-related proline-rich transmembrane protein 2 (PRRT2) by calpain in mouse primary cortical neurons

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Title: Activity-dependent cleavage of dyskinesia-related proline-rich transmembrane protein 2 (PRRT2) by calpain in mouse primary cortical neurons
Authors: Hatta, Daisuke / Shirotani, Keiro / Hori, Yuma / Kurotaki, Naohiro / Iwata, Nobuhisa
Issue Date: 20-Nov-2019
Publisher: Wiley
Citation: FASEB journal, 34(1), pp.180-191; 2020
Abstract: Mutations of PRRT2 (proline-rich transmembrane protein 2) cause several neurological disorders, represented by paroxysmal kinesigenic dyskinesia (PKD), which is characterized by attacks of involuntary movements triggered by sudden voluntary movements. PRRT2 is reported to suppress neuronal excitation, but it is unclear how the function of PRRT2 is modulated during neuronal excitation. We found that PRRT2 is processed to a 12 kDa carboxy-terminal fragment (12K-CTF) by calpain, a calcium-activated cysteine protease, in a neuronal activity-dependent manner, predominantly via NMDA receptors or voltage-gated calcium channels. Furthermore, we clarified that 12K-CTF is generated by sequential cleavages at Q220 and S244. The amino-terminal fragment (NTF) of PRRT2, which corresponds to PKD-related truncated mutants, is not detected, probably due to rapid cleavage at multiple positions. Given that 12K-CTF lacks most of the proline-rich domain, this cleavage might be involved in the activity-dependent enhancement of neuronal excitation perhaps through transient retraction of PRRT2's function. Therefore, PRRT2 might serve as a buffer for neuronal excitation, and lack of this function in PKD patients might cause neuronal hyperexcitability in their motor circuits.
Keywords: proteolysis / NMDA receptor / glutamate / calcium signaling / neuronal excitation
URI: http://hdl.handle.net/10069/39661
ISSN: 08926638
DOI: 10.1096/fj.201902148R
Rights: © 2019 Federation of American Societies for Experimental Biology. This is the peer reviewed version of the following article: FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 34(1), pp.180-191; 2020, which has been published in final form at 10.1096/fj.201902148R. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/39661

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