title: Calcineurin Aγ is a Functional Phosphatase That Modulates Synaptic Vesicle Endocytosis.
abstract: Variation in PPP3CC, the gene that encodes the γ isoform of the calcineurin catalytic subunit, has been reported to be associated with schizophrenia. Because of its low expression level in most tissues, there has been little research devoted to the specific function of the calcineurin Aγ (CNAγ) versus the calcineurin Aα (CNAα) and calcineurin Aβ (CNAβ) catalytic isoforms. Consequently, we have a limited understanding of the role of altered CNAγ function in psychiatric disease. In this study, we demonstrate that CNAγ is present in the rodent and human brain and dephosphorylates a presynaptic substrate of calcineurin. Through a combination of immunocytochemistry and immuno-EM, we further show that CNAγ is localized to presynaptic terminals in hippocampal neurons. Critically, we demonstrate that RNAi-mediated knockdown of CNAγ leads to a disruption of synaptic vesicle cycling in cultured rat hippocampal neurons. These data indicate that CNAγ regulates a critical aspect of synaptic vesicle cycling and suggest that variation in PPP3CC may contribute to psychiatric disease by altering presynaptic function.
authors.affiliation: From the Galenea Corporation, Wakefield, MA 01880.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Cottrell
authors.affiliation: From the Galenea Corporation, Wakefield, MA 01880.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: the Department of Physiology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, 02447, South Korea.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Kyung
authors.affiliation: From the Galenea Corporation, Wakefield, MA 01880.
authors.forename: Crystle J
authors.initials: CJ
authors.lastname: Ashford
authors.affiliation: From the Galenea Corporation, Wakefield, MA 01880.
authors.forename: James J
authors.initials: JJ
authors.lastname: Mann
authors.affiliation: the Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, and.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.affiliation: the Department of Biochemistry, Weill Cornell Medical College, New York, New York 10021.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Ryan
authors.affiliation: the Department of Physiology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, 02447, South Korea. Electronic address: sunghyunkim@khu.ac.kr.
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: From the Galenea Corporation, Wakefield, MA 01880,. Electronic address: dgerber@galenea.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gerber
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004705:Endocytosis; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000201:enzymology; D051381:Rats; D013572:Synaptic Vesicles / Q000201:enzymology* / Q000235:genetics
chemical_list: D019703:Calcineurin; C525674:PPP3CB protein, human; C581051:PPP3CB protein, rat; C525675:PPP3CC protein, human
keywords: calcineurin; neuron; schizophrenia; synapse; vesicles