title: Endogenous α2A-Adrenoceptor-Operated Sympathoadrenergic Tones Attenuate Insulin Secretion via cAMP/TRPM2 Signaling.
abstract: In pancreatic β-cells, pharmacological concentrations of catecholamines, including adrenaline, have been used to inhibit insulin release and explore the multiple mechanisms involved. However, the significance of these signaling pathways for physiological adrenergic functions in β-cells is largely unknown. In the process of glucose-induced insulin secretion, opening of background current through nonselective cation channels (NSCCs) might facilitate membrane depolarization by closure of the ATP-sensitive K+channels. Here, we examined whether physiological insulinostatic adrenaline action is mediated via the transient receptor potential melastatin 2 (TRPM2) channel, a type of NSCC, in β-cells. Results showed that physiological concentrations of adrenaline strongly suppressed glucose-induced and incretin-potentiated cAMP production and insulin secretion and inhibited NSCCs current and membrane excitability via the α2A-adrenoceptor in wild-type mice; however, insulin secretion was not attenuated in TRPM2-knockout (KO) mice. Administration of yohimbine, an α2-adrenoceptor antagonist, failed to affect glucose tolerance in TRPM2-KO mice, in contrast to an improved glucose tolerance in wild-type mice receiving the antagonist. The current study demonstrated that a physiological concentration of adrenaline attenuates insulin release via coupling of α2A-adrenoceptor to cAMP/TRPM2 signaling, thereby providing a potential therapeutic tool to treat patients with type 2 diabetes.
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Kiyonori
authors.identifier: 0000-0001-8514-4481
authors.initials: K
authors.lastname: Ito
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan dezaki@jichi.ac.jp mkakei@jichi.ac.jp.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Hodaka
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Miura
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan.
authors.forename: Rauza Sukma
authors.initials: RS
authors.lastname: Rita
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ookawara
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.|Minamiuonuma City Hospital, Niigata, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tabei
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.|Nerima Hikarigaoka Hospital, Tokyo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kawakami
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hara
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishita
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
authors.affiliation: First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan dezaki@jichi.ac.jp mkakei@jichi.ac.jp.|Saitama Citizens Medical Center, Saitama, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004837:Epinephrine / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005951:Glucose Tolerance Test; D054795:Incretins / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D013566:Sympathomimetics / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000235:genetics*
chemical_list: C547769:Adra2a protein, mouse; D054795:Incretins; D007328:Insulin; D018341:Receptors, Adrenergic, alpha-2; D013566:Sympathomimetics; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D000242:Cyclic AMP; D005947:Glucose; D004837:Epinephrine