Prion protein interacts with the metabotropic glutamate receptor 1 and regulates the organization of Ca2+ signaling

Takehiro Matsubara; Katsuya Satoh; Takujiro Homma; Takehiro Nakagaki; Naohiro Yamaguchi; Ryuichiro Atarashi; Yuka Sudo; Yasuhito Uezono; Daisuke Ishibashi; Noriyuki Nishida

doi:10.1016/j.bbrc.2020.02.102

Prion protein interacts with the metabotropic glutamate receptor 1 and regulates the organization of Ca²⁺ signaling

Biochem Biophys Res Commun. 2020 Apr 30;525(2):447-454. doi: 10.1016/j.bbrc.2020.02.102. Epub 2020 Feb 24.

Authors

Affiliations

¹ Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Japan; Okayama University Hospital Biobank, Okayama University Hospital, Okayama, Japan.
² Department of Locomotive Rehabilitation Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
³ Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Japan; Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Japan.
⁴ Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Japan.
⁵ Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Japan; Division of Microbiology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Japan.
⁶ Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Japan; Cancer Pathophysiology Division, National Cancer Center, Research Institute, Japan.
⁷ Cancer Pathophysiology Division, National Cancer Center, Research Institute, Japan.
⁸ Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Japan. Electronic address: dishi@nagasaki-u.ac.jp.

PMID: 32107004
DOI: 10.1016/j.bbrc.2020.02.102

Abstract

Cellular prion protein (PrP) is a membrane protein that is highly conserved among mammals and mainly expressed on the cell surface of neurons. Despite its reported interactions with various membrane proteins, no functional studies have so far been carried out on it, and its physiological functions remain unclear. Neuronal cell death has been observed in a PrP-knockout mouse model expressing Doppel protein, suggesting that PrP might be involved in Ca²⁺ signaling. In this study, we evaluated the binding of PrP to metabotropic glutamate receptor 1 (mGluR1) and found that wild-type PrP (PrP-wt) and mGluR1 co-immunoprecipitated in dual-transfected Neuro-2a (N2a) cells. Fluorescence resonance energy transfer analysis revealed an energy transfer between mGluR1-Cerulean and PrP-Venus. In order to determine whether PrP can modulate mGluR1 signaling, we performed Ca²⁺ imaging analyses following repetitive exposure to an mGluR1 agonist. Agonist stimulation induced synchronized Ca²⁺ oscillations in cells coexpressing PrP-wt and mGluR1. In contrast, N2a cells expressing PrP-ΔN failed to show ligand-dependent regulation of mGluR1-Ca²⁺ signaling, indicating that PrP can bind to mGluR1 and modulate its function to prevent irregular Ca²⁺ signaling and that its N-terminal region functions as a molecular switch during Ca²⁺ signaling.

Keywords: Ca(2+); Cellular prion protein; Prion diseases; mGluR1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium / metabolism
Calcium Signaling*
Cell Line
Mice
Neurons / metabolism
Prion Proteins / metabolism*
Protein Interaction Maps
Receptors, Metabotropic Glutamate / metabolism*

Substances

Prion Proteins
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor type 1
Calcium