title: Cyclic ADP-Ribose and Heat Regulate Oxytocin Release via CD38 and TRPM2 in the Hypothalamus during Social or Psychological Stress in Mice.
abstract: Hypothalamic oxytocin (OT) is released into the brain by cyclic ADP-ribose (cADPR) with or without depolarizing stimulation. Previously, we showed that the intracellular free calcium concentration ([Ca(2+)]i) that seems to trigger OT release can be elevated by β-NAD(+), cADPR, and ADP in mouse oxytocinergic neurons. As these β-NAD(+) metabolites activate warm-sensitive TRPM2 cation channels, when the incubation temperature is increased, the [Ca(2+)]i in hypothalamic neurons is elevated. However, it has not been determined whether OT release is facilitated by heat in vitro or hyperthermia in vivo in combination with cADPR. Furthermore, it has not been examined whether CD38 and TRPM2 exert their functions on OT release during stress or stress-induced hyperthermia in relation to the anxiolytic roles and social behaviors of OT under stress conditions. Here, we report that OT release from the isolated hypothalami of male mice in culture was enhanced by extracellular application of cADPR or increasing the incubation temperature from 35°C to 38.5°C, and simultaneous stimulation showed a greater effect. This release was inhibited by a cADPR-dependent ryanodine receptor inhibitor and a nonspecific TRPM2 inhibitor. The facilitated release by heat and cADPR was suppressed in the hypothalamus isolated from CD38 knockout mice and CD38- or TRPM2-knockdown mice. In the course of these experiments, we noted that OT release differed markedly between individual mice under stress with group housing. That is, when male mice received cage-switch stress and eliminated due to their social subclass, significantly higher levels of OT release were found in subordinates compared with ordinates. In mice exposed to anxiety stress in an open field, the cerebrospinal fluid (CSF) OT level increased transiently at 5 min after exposure, and the rectal temperature also increased from 36.6°C to 37.8°C. OT levels in the CSF of mice with lipopolysaccharide-induced fever (+0.8°C) were higher than those of control mice. The TRPM2 mRNA levels and immunoreactivities increased in the subordinate group with cage-switch stress. These results showed that cADPR/CD38 and heat/TRPM2 are co-regulators of OT secretion and suggested that CD38 and TRPM2 are potential therapeutic targets for OT release in psychiatric diseases caused by social stress.
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Jing
authors: J
authors: Zhong
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Sarwat
authors: S
authors: Amina
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Mingkun
authors: M
authors: Liang
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Shirin
authors: S
authors: Akther
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Teruko
authors: T
authors: Yuhi
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Tomoko
authors: T
authors: Nishimura
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Chiharu
authors: C
authors: Tsuji
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Takahiro
authors: T
authors: Tsuji
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Hong-Xiang
authors: HX
authors: Liu
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Minako
authors: M
authors: Hashii
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Kazumi
authors: K
authors: Furuhara
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University Kanazawa, Japan.
authors: Shigeru
authors: S
authors: Yokoyama
authors: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences Kanazawa, Japan.
authors: Yasuhiko
authors: Y
authors: Yamamoto
authors: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical SciencesKanazawa, Japan; Department of Biochemistry, Tohoku University Graduate School of MedicineSendai, Japan.
authors: Hiroshi
authors: H
authors: Okamoto
authors: School of Chemical Biology and Biotechnology, Peking University Graduate School Shenzhen, China.
authors: Yong Juan
authors: YJ
authors: Zhao
authors: School of Chemical Biology and Biotechnology, Peking University Graduate School Shenzhen, China.
authors: Hon Cheung
authors: HC
authors: Lee
authors: Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences Okazaki, Japan.
authors: Makoto
authors: M
authors: Tominaga
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa UniversityKanazawa, Japan; Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical UniversityKrasnoyarsk, Russia.
authors: Olga
authors: O
authors: Lopatina
authors: Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa UniversityKanazawa, Japan; Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical UniversityKrasnoyarsk, Russia.
authors: Haruhiro
authors: H
authors: Higashida
keywords: NAD; autism; cyclic ADP-ribose; hyperthermia; oxytocin; secretion; stress