title: Junctophilin 3 expresses in pancreatic beta cells and is required for glucose-stimulated insulin secretion.
abstract: It is well accepted that junctophilin (JPHs) isoforms act as a physical bridge linking plasma membrane and endoplasmic reticulum (ER) for channel crosstalk in excitable cells. Our purpose is to investigate whether JPHs are involved in the proper communication between Ca(2+) influx and subsequent Ca(2+) amplification in pancreatic beta cells, thereby participating in regulating insulin secretion. The expression of JPH isoforms was examined in human and mouse pancreatic tissues, and JPH3 expression was found in both the beta cells. In mice, knockdown of Jph3 (si-Jph3) in islets decreased glucose-stimulated insulin secretion (GSIS) accompanied by mitochondrial function impairment. Si-Jph3 lowered the insulin secretory response to Ca(2+) signaling in the presence of glucose, and reduced [Ca(2+)]c transient amplitude triggered by caffeine. Si-Jph3 also attenuated mitofusin 2 expression, thereby disturbing the spatial organization of ER-mitochondria contact in islets. These results suggest that the regulation of GSIS by the KATP channel-independent pathways is partly impaired due to decrease of JPH3 expression in mouse islets. JPH3 also binds to type 2 ryanodine receptors (RyR2) in mouse and human pancreatic tissues, which might contribute to Ca(2+) release amplification in GSIS. This study demonstrates some previously unrecognized findings in pancreatic tissues: (1) JPH3 expresses in mouse and human beta cells; (2) si-Jph3 in mouse primary islets impairs GSIS in vitro; (3) impairment in GSIS in si-Jph3 islets is due to changes in RyR2-[Ca(2+)]c transient amplitude and ER-mitochondria contact.
authors.affiliation: Insititute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Insititute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Z-F
authors.initials: ZF
authors.lastname: Pan
authors.affiliation: Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Cardiovascular Key Laboratory of Zhejiang Province, The 2nd Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Insititute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: B-W
authors.initials: BW
authors.lastname: Wu
authors.affiliation: Insititute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
authors.forename: M-X
authors.initials: MX
authors.lastname: Kang
authors.affiliation: The Population Council at the Rockefeller University, New York 10021, NY, USA.|Institute of Reproductive Biomedicine, the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou 325027, China.
authors.forename: R-S
authors.initials: RS
authors.lastname: Ge
authors.affiliation: Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Cardiovascular Key Laboratory of Zhejiang Province, The 2nd Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Hu
authors.affiliation: Insititute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Insititute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: L-J
authors.initials: LJ
authors.lastname: Ge
authors.affiliation: Insititute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: D-Y
authors.initials: DY
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Insititute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.|Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Lou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D007328:Insulin; D008565:Membrane Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering; C412507:junctophilin; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; D005947:Glucose; D002118:Calcium