title: Calcium release channel RyR2 regulates insulin release and glucose homeostasis.
abstract: The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.forename: Gennaro
authors.initials: G
authors.lastname: Pagano
authors.forename: Celestino
authors.initials: C
authors.lastname: Sardu
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xie
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Salvatore Luca
authors.initials: SL
authors.lastname: D'Ascia
authors.forename: Michele
authors.initials: M
authors.lastname: Cannone
authors.forename: Nicola
authors.initials: N
authors.lastname: Marziliano
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D017136:Ion Transport; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008820:Mice, Obese; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D020125:Mutation, Missense; D015538:Nitrosation; D010084:Oxidation-Reduction; D017354:Point Mutation; D019837:Ryanodine Receptor Calcium Release Channel; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D007328:Insulin; D019837:Ryanodine Receptor Calcium Release Channel; D005934:Glucagon; D005947:Glucose; D002118:Calcium
references.citation: J Cardiovasc Transl Res. 2014 Apr;7(3):362-8
references.pmid: 24500410
references.citation: Diabetologia. 2010 Jun;53(6):1019-32
references.pmid: 20225132
references.citation: J Biol Chem. 2014 May 2;289(18):12435-45
references.pmid: 24627477
references.citation: Circ Arrhythm Electrophysiol. 2012 Oct;5(5):1044-52
references.pmid: 23022705
references.citation: Cell. 2001 Jun 15;105(6):745-55
references.pmid: 11440717
references.citation: Diabetes. 2014 Oct;63(10):3163-5
references.pmid: 25249639
references.citation: Diabetologia. 2005 Feb;48(2):282-9
references.pmid: 15654602
references.citation: Philos Trans R Soc Lond B Biol Sci. 2005 Dec 29;360(1464):2211-25
references.pmid: 16321791
references.citation: Diabetes. 2006 Dec;55 Suppl 2:S16-23
references.pmid: 17130640
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1559-64
references.pmid: 20080623
references.citation: Diabetes. 2006 Feb;55(2):441-51
references.pmid: 16443779
references.citation: Diabetes. 2005 Feb;54(2):452-61
references.pmid: 15677503
references.citation: J Clin Invest. 2003 Dec;112(12):1831-42
references.pmid: 14679178
references.citation: J Clin Invest. 2009 Nov;119(11):3246-56
references.pmid: 19805912
references.citation: Endocrinology. 2014 Mar;155(3):758-68
references.pmid: 24424032
references.citation: Mol Cell Endocrinol. 2012 Apr 28;353(1-2):128-37
references.pmid: 21784130
references.citation: J Clin Invest. 2011 Jun;121(6):2422-6
references.pmid: 21555853
references.citation: J Biol Chem. 2008 Apr 11;283(15):9909-16
references.pmid: 18174159
references.citation: JAMA Intern Med. 2015 Apr;175(4):657
references.pmid: 25844751
references.citation: Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):13924-9
references.pmid: 25201977
references.citation: Hypertension. 2010 Oct;56(4):696-704
references.pmid: 20660817
references.citation: J Clin Invest. 2003 Apr;111(8):1147-60
references.pmid: 12697734
references.citation: Biochem Biophys Res Commun. 2008 Jul 11;371(4):735-40
references.pmid: 18466757
references.citation: Endocrinology. 2013 Sep;154(9):3077-88
references.pmid: 23836031
references.citation: Circulation. 2004 Jun 29;109(25):3208-14
references.pmid: 15197150
references.citation: Diabetes. 2006 Jun;55(6):1705-12
references.pmid: 16731833
references.citation: Diabetologia. 2014 Aug;57(8):1601-10
references.pmid: 24893864
references.citation: J Mol Cell Cardiol. 2013 Nov;64:120-3
references.pmid: 24041536
references.citation: Int J Cardiol. 2015 Feb 1;180:228-36
references.pmid: 25463374
references.citation: Cell Signal. 2012 Feb;24(2):468-75
references.pmid: 21983013
references.citation: Nat Genet. 2012 Mar;44(3):297-301
references.pmid: 22286214
references.citation: Cell Calcium. 2014 Nov;56(5):340-61
references.pmid: 25239387
references.citation: Adv Exp Med Biol. 2010;654:235-59
references.pmid: 20217501
references.citation: JAMA. 2012 Mar 21;307(11):1137; author reply 1138
references.pmid: 22436947
references.citation: Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15250-5
references.pmid: 25288763
references.citation: J Clin Invest. 2013 Jan;123(1):46-52
references.pmid: 23281409
references.citation: J Clin Endocrinol Metab. 2015 Jan;100(1):E1-10
references.pmid: 25295624
references.citation: Cell. 1994 May 20;77(4):513-23
references.pmid: 7514503
references.citation: Mol Pharmacol. 2012 Jan;81(1):53-62
references.pmid: 21989257
references.citation: Diabetes. 2012 Mar;61(3):692-701
references.pmid: 22315324
references.citation: Nat Rev Endocrinol. 2013 Nov;9(11):660-9
references.pmid: 24042324
references.citation: Nat Commun. 2010 Nov 23;1:127
references.pmid: 21119640
references.citation: Sci Rep. 2014;4:7425
references.pmid: 25502776
references.citation: Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E585-99
references.pmid: 23820623
references.citation: Mol Biol Cell. 2012 Oct;23(19):3851-62
references.pmid: 22875990
references.citation: Diabetes. 2015 Feb;64(2):565-72
references.pmid: 25187365
references.citation: FEBS Lett. 2012 Jan 2;586(1):89-95
references.pmid: 22154597
references.citation: J Clin Invest. 2014 Sep;124(9):4102-14
references.pmid: 25133430
references.citation: Nat Genet. 2014 Mar;46(3):234-44
references.pmid: 24509480
references.citation: FASEB J. 2004 May;18(7):878-80
references.pmid: 15033925
references.citation: J Am Heart Assoc. 2012 Aug;1(4):e001081
references.pmid: 23130158
references.citation: J Biol Chem. 2014 Mar 28;289(13):9182-94
references.pmid: 24554722
references.citation: J Clin Invest. 1998 May 15;101(10):2215-22
references.pmid: 9593777
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2198-202
references.pmid: 18268335
references.citation: FASEB J. 2003 Feb;17(2):301-3
references.pmid: 12475892
references.citation: Nature. 2007 Feb 22;445(7130):881-5
references.pmid: 17293876
references.citation: J Clin Invest. 2001 Oct;108(7):1015-22
references.pmid: 11581302
references.citation: Dev Cell. 2003 Jul;5(1):73-83
references.pmid: 12852853
references.citation: Diabetes. 2002 Feb;51 Suppl 1:S37-42
references.pmid: 11815456
references.citation: Nat Cell Biol. 2007 Apr;9(4):453-60
references.pmid: 17369816
references.citation: Nature. 2015 Jan 1;517(7532):44-9
references.pmid: 25470061
references.citation: J Biol Chem. 1998 Sep 18;273(38):24457-64
references.pmid: 9733737
references.citation: Neurology. 2012 Mar 13;78(11):840
references.pmid: 22411960
references.citation: PLoS One. 2012;7(1):e29202
references.pmid: 22238593
references.citation: Diabetologia. 2012 May;55(5):1366-79
references.pmid: 22396011
references.citation: Nature. 2010 Sep 16;467(7313):291-6
references.pmid: 20693986
references.citation: PLoS Med. 2014 May;11(5):e1001647
references.pmid: 24845081
references.citation: J Clin Invest. 1997 Dec 15;100(12):3164-72
references.pmid: 9399964
references.citation: N Engl J Med. 2001 Sep 13;345(11):790-7
references.pmid: 11556298
references.citation: J Clin Invest. 2006 Jul;116(7):1802-12
references.pmid: 16823478
references.citation: Nat Genet. 2010 Feb;42(2):142-8
references.pmid: 20081857
references.citation: J Clin Invest. 1999 Dec;104(12):R69-75
references.pmid: 10606633
references.citation: Curr Mol Pharmacol. 2015;8(2):206-22
references.pmid: 25966694
references.citation: Protoplasma. 2012 Feb;249 Suppl 1:S49-58
references.pmid: 22105567