title: Calcyon stimulates neuregulin 1 maturation and signaling.
abstract: Neuregulin1 (NRG1) is a single transmembrane protein that plays a critical role in neural development and synaptic plasticity. Both NRG1 and its receptor, ErbB4, are well-established risk genes of schizophrenia. The NRG1 ecto-domain (ED) binds and activates ErbB4 following proteolytic cleavage of pro-NRG1 precursor protein. Although several studies have addressed the function of NRG1 in brain, very little is known about the cleavage and shedding mechanism. Here we show that the neuronal vesicular protein calcyon is a potent activator and key determinant of NRG1 ED cleavage and shedding. Calcyon stimulates clathrin-mediated endocytosis and endosomal targeting; and its levels are elevated in postmortem brains of schizophrenics. Overexpression of calcyon stimulates NRG1 cleavage and signaling in vivo, and as a result, GABA transmission is enhanced in calcyon overexpressing mice. Conversely, NRG1 cleavage, ErbB4 activity and GABA transmission are decreased in calcyon null mice. Moreover, stimulation of NRG1 cleavage by calcyon was recapitulated in HEK 293 cells suggesting the mechanism involved is cell-autonomous. Finally, studies with site-specific mutants in calcyon and inhibitors for the major sheddases indicate that the stimulatory effects of calcyon on NRG1 cleavage and shedding depend on clathrin-mediated endocytosis, β-secretase 1, and interaction with clathrin adaptor proteins. Together these results identify a novel mechanism for NRG1 cleavage and shedding.
authors.affiliation: Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, China.|Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.
authors.forename: D-M
authors.initials: DM
authors.lastname: Yin
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.|Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.|Institute of Life Science, Nanchang University, Nanchang, China.
authors.forename: H
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sathyamurthy
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Lin
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.|Department of Neurology.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: W-C
authors.initials: WC
authors.lastname: Xiong
authors.affiliation: Institute of Life Science, Nanchang University, Nanchang, China.
authors.forename: B-M
authors.initials: BM
authors.lastname: Li
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA, USA.|Department of Neurology.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bergson
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D018929:Cell Culture Techniques; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism*; D018757:GABA Modulators / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity; D066247:Receptor, ErbB-4 / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology
chemical_list: D018757:GABA Modulators; D008565:Membrane Proteins; C094131:NRG1 protein, human; D020890:Neuregulin-1; C405464:calcyon; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human