title: The β-cell GHSR and downstream cAMP/TRPM2 signaling account for insulinostatic and glycemic effects of ghrelin.
abstract: Gastric hormone ghrelin regulates insulin secretion, as well as growth hormone release, feeding behavior and adiposity. Ghrelin is known to exert its biological actions by interacting with the growth hormone secretagogue-receptor (GHSR) coupled to G(q/11)-protein signaling. By contrast, ghrelin acts on pancreatic islet β-cells via Gi-protein-mediated signaling. These observations raise a question whether the ghrelin action on islet β-cells involves atypical GHSR and/or distinct signal transduction. Furthermore, the role of the β-cell GHSR in the systemic glycemic effect of ghrelin still remains to be defined. To address these issues, the present study employed the global GHSR-null mice and those re-expressing GHSR selectively in β-cells. We here report that ghrelin attenuates glucose-induced insulin release via direct interaction with ordinary GHSR that is uniquely coupled to novel cAMP/TRPM2 signaling in β-cells, and that this β-cell GHSR with unique insulinostatic signaling largely accounts for the systemic effects of ghrelin on circulating glucose and insulin levels. The novel β-cell specific GHSR-cAMP/TRPM2 signaling provides a potential therapeutic target for the treatment of type 2 diabetes.
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.|Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kurashina
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.affiliation: Department of Internal Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Omiya 1-847, Saitama 337-8503, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Rauza
authors.initials: R
authors.lastname: Sukma Rita
authors.affiliation: Department of Internal Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Omiya 1-847, Saitama 337-8503, Japan.
authors.forename: Kiyonori
authors.initials: K
authors.lastname: Ito
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Taguchi
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Miura
authors.affiliation: Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, Okazaki, Aichi 444-8787, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.affiliation: Department of Internal Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Omiya 1-847, Saitama 337-8503, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.|Department of Development Physiology, Division of Adaptation Development, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D015870:Gene Expression; D054439:Ghrelin / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D054440:Receptors, Ghrelin; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium