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Diabetologia

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01.02.2013 | Article

The human L-type calcium channel Ca_v1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

verfasst von: T. M. Reinbothe, S. Alkayyali, E. Ahlqvist, T. Tuomi, B. Isomaa, V. Lyssenko, E. Renström

Erschienen in: Diabetologia | Ausgabe 2/2013

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Abstract

Aims/hypothesis

Voltage-gated calcium channels of the L-type have been shown to be essential for rodent pancreatic beta cell function, but data about their presence and regulation in humans are incomplete. We therefore sought to elucidate which L-type channel isoform is functionally important and its association with inherited diabetes-related phenotypes.

Methods

Beta cells of human islets from cadaver donors were enriched using FACS to study the expression of the genes encoding voltage-gated calcium channel (Ca_v)1.2 and Ca_v1.3 by absolute quantitative PCR in whole human and rat islets, as well as in clonal cells. Single-cell exocytosis was monitored as increases in cell capacitance after treatment with small interfering (si)RNA against CACNA1D (which encodes Ca_v1.3). Three single nucleotide polymorphisms (SNPs) were genotyped in 8,987 non-diabetic and 2,830 type 2 diabetic individuals from Finland and Sweden and analysed for associations with type 2 diabetes and insulin phenotypes.

Results

In FACS-enriched human beta cells, CACNA1D mRNA expression exceeded that of CACNA1C (which encodes Ca_v1.2) by approximately 60-fold and was decreased in islets from type 2 diabetes patients. The latter coincided with diminished secretion of insulin in vitro. CACNA1D siRNA reduced glucose-stimulated insulin release in INS-1 832/13 cells and exocytosis in human beta cells. Phenotype/genotype associations of three SNPs in the CACNA1D gene revealed an association between the C allele of the SNP rs312480 and reduced mRNA expression, as well as decreased insulin secretion in vivo, whereas both rs312486/G and rs9841978/G were associated with type 2 diabetes.

Conclusion/interpretation

We conclude that the L-type calcium channel Ca_v1.3 is important in human glucose-induced insulin secretion, and common variants in CACNA1D might contribute to type 2 diabetes.

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Rorsman P (1997) The pancreatic beta-cell as a fuel sensor: an electrophysiologist’s viewpoint. Diabetologia 40:487–495PubMedCrossRef

Davalli AM, Biancardi E, Pollo A et al (1996) Dihydropyridine-sensitive and -insensitive voltage-operated calcium channels participate in the control of glucose-induced insulin release from human pancreatic beta cells. J Endocrinol 150:195–203PubMedCrossRef

Drews G, Krippeit-Drews P, Dufer M (2010) Electrophysiology of islet cells. Adv Exp Med Biol 654:115–163PubMedCrossRef

Seisenberger C, Specht V, Welling A et al (2000) Functional embryonic cardiomyocytes after disruption of the L-type alpha1C (Cav1.2) calcium channel gene in the mouse. J Biol Chem 275:39193–39199PubMedCrossRef

Barg S, Eliasson L, Renstrom E, Rorsman P (2002) A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells. Diabetes 51(Suppl 1):S74–S82PubMedCrossRef

Vignali S, Leiss V, Karl R, Hofmann F, Welling A (2006) Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A- and B-cells. J Physiol 572:691–706PubMed

Schulla V, Renstrom E, Feil R et al (2003) Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca2+ channel null mice. EMBO J 22:3844–3854PubMedCrossRef

Namkung Y, Skrypnyk N, Jeong MJ et al (2001) Requirement for the L-type Ca(2+) channel alpha(1D) subunit in postnatal pancreatic beta cell generation. J Clin Investig 108:1015–1022PubMed

Dreja T, Jovanovic Z, Rasche A et al (2009) Diet-induced gene expression of isolated pancreatic islets from a polygenic mouse model of the metabolic syndrome. Diabetologia 53:309–320PubMedCrossRef

10.

Koschak A, Reimer D, Huber I et al (2001) alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. J Biol Chem 276:22100–22106PubMedCrossRef

11.

Sinnegger-Brauns MJ, Huber IG, Koschak A et al (2009) Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol Pharmacol 75:407–414PubMedCrossRef

12.

Seino S (1995) CACN4, the major alpha 1 subunit isoform of voltage-dependent calcium channels in pancreatic beta-cells: a minireview of current progress. Diabetes Res Clin Pract 28(Suppl):S99–S103PubMedCrossRef

13.

Iwashima Y, Pugh W, Depaoli AM et al (1993) Expression of calcium channel mRNAs in rat pancreatic islets and downregulation after glucose infusion. Diabetes 42:948–955PubMedCrossRef

14.

Striessnig J, Bolz HJ, Koschak A (2010) Channelopathies in Ca(v)1.1, Ca(v)1.3, and Ca(v)1.4 voltage-gated L-type Ca(2+) channels. Pflugers Arch 460:361–374PubMedCrossRef

15.

Braun M, Ramracheya R, Bengtsson M et al (2008) Voltage-gated ion channels in human pancreatic beta-cells: electrophysiological characterization and role in insulin secretion. Diabetes 57:1618–1628PubMedCrossRef

16.

Yamada Y, Masuda K, Li Q et al (1995) The structures of the human calcium channel alpha 1 subunit (CACNL1A2) and beta subunit (CACNLB3) genes. Genomics 27:312–319PubMedCrossRef

17.

Yamada Y, Kuroe A, Li Q et al (2001) Genomic variation in pancreatic ion channel genes in Japanese type 2 diabetic patients. Diabetes Metabol Res Rev 17:213–216CrossRef

18.

Saxena R, Voight BF, Lyssenko V et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336PubMedCrossRef

19.

Voight BF, Scott LJ, Steinthorsdottir V et al (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579–589PubMedCrossRef

20.

Reinbothe TM, Ivarsson R, Li DQ et al (2009) Glutaredoxin-1 mediates NADPH-dependent stimulation of calcium-dependent insulin secretion. Mol Endocrinol 23:893–900PubMedCrossRef

21.

Lukowiak B, Vandewalle B, Riachy R et al (2001) Identification and purification of functional human beta-cells by a new specific zinc-fluorescent probe. J Histochem Cytochem Offic J Histochem Soc 49:519–528CrossRef

22.

Kirkpatrick CL, Marchetti P, Purrello F et al (2010) Type 2 diabetes susceptibility gene expression in normal or diabetic sorted human alpha and beta cells: correlations with age or BMI of islet donors. PLoS One 5:e11053PubMedCrossRef

23.

Jonsson A, Isomaa B, Tuomi T et al (2009) A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion. Diabetes 58:2409–2413PubMedCrossRef

24.

Lyssenko V, Eliasson L, Kotova O et al (2011) Pleiotropic effects of GIP on islet function involve osteopontin. Diabetes 60:2424–2433PubMedCrossRef

25.

Groop L, Forsblom C, Lehtovirta M et al (1996) Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 45:1585–1593PubMedCrossRef

26.

Pyykkönen A-J, Räikkönen K, Tuomi T, Eriksson JG, Groop L, Isomaa B (2010) Stressful life events and the metabolic syndrome. Diabetes Care 33:378–384PubMedCrossRef

27.

Lindholm E, Agardh E, Tuomi T, Groop L, Agardh CD (2001) Classifying diabetes according to the new WHO clinical stages. Eur J Epidemiol 17:983–989PubMedCrossRef

28.

Berglund G, Elmstahl S, Janzon L, Larsson SA (1993) The Malmo Diet and Cancer study. Design and feasibility. J Intern Med 233:45–51PubMedCrossRef

29.

World Health Organisation (2006) Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF Consultation. Available from http://www.who.int/entity/diabetes/publications/. Accessed 11 June 2011

30.

Pickering BM, Willis AE (2005) The implications of structured 5′ untranslated regions on translation and disease. Semin Cell Dev Biol 16:39–47PubMedCrossRef

31.

Kamide K, Yang J, Matayoshi T et al (2009) Genetic polymorphisms of L-type calcium channel alpha1C and alpha1D subunit genes are associated with sensitivity to the antihypertensive effects of L-type dihydropyridine calcium-channel blockers. Circ J 73:732–740PubMedCrossRef

32.

Rosengren AH, Jokubka R, Tojjar D et al (2010) Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 327:217–220PubMedCrossRef

33.

Taneera J, Jin Z, Jin Y, et al. (2012) γ-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes. Diabetologia 55:1985–1994

34.

Taneera J, Lang S, Sharma A et al (2012) A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metabol 16:122–134CrossRef

35.

Bigos KL, Mattay VS, Callicott JH et al (2010) Genetic variation in CACNA1C affects brain circuitries related to mental illness. Arch Gen Psychiatry 67:939–945PubMedCrossRef

36.

Sklar P, Smoller JW, Fan J et al (2008) Whole-genome association study of bipolar disorder. Mol Psychiatr 13:558–569CrossRef

37.

Green EK, Grozeva D, Jones I et al (2009) The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatr 15:1016–1022CrossRef

38.

Hohmeier HE, Mulder H, Chen G, Henkel-Rieger R, Prentki M, Newgard CB (2000) Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes 49:424–430PubMedCrossRef

39.

Platzer J, Engel J, Schrott-Fischer A et al (2000) Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102:89–97PubMedCrossRef

40.

Sinnegger-Brauns MJ, Hetzenauer A, Huber IG et al (2004) Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca2+ channels. J Clin Investig 113:1430–1439PubMed

41.

Mangoni ME, Nargeot J (2008) Genesis and regulation of the heart automaticity. Physiol Rev 88:919–982PubMedCrossRef

42.

Comunanza V, Marcantoni A, Vandael DH et al (2011) CaV1.3 as pacemaker channels in adrenal chromaffin cells: specific role on exo- and endocytosis? Channels 4:440–446

43.

Misler S, Dickey A, Barnett DW (2005) Maintenance of stimulus-secretion coupling and single beta-cell function in cryopreserved-thawed human islets of Langerhans. Pflugers Arch 450:395–404PubMedCrossRef

44.

Brandt A, Striessnig J, Moser T (2003) CaV1.3 channels are essential for development and presynaptic activity of cochlear inner hair cells. J Neurosci 23:10832–10840PubMed

45.

Ahlgren U, Gotthardt M (2010) Approaches for imaging islets: recent advances and future prospects. Adv Exp Med Biol 654:39–57PubMedCrossRef

46.

Nitert MD, Nagorny CL, Wendt A, Eliasson L, Mulder H (2008) CaV1.2 rather than CaV1.3 is coupled to glucose-stimulated insulin secretion in INS-1 832/13 cells. J Mol Endocrinol 41:1–11PubMedCrossRef

47.

Hulme JT, Konoki K, Lin TW et al (2005) Sites of proteolytic processing and noncovalent association of the distal C-terminal domain of CaV1.1 channels in skeletal muscle. Proc Natl Acad Sci U S A 102:5274–5279PubMedCrossRef

48.

Satin J, Schroder EA, Crump SM (2011) L-type calcium channel auto-regulation of transcription. Cell Calcium 49:306–313PubMedCrossRef

49.

Bjorklund A, Lansner A, Grill VE (2000) Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation. Diabetes 49:1840–1848PubMedCrossRef

50.

Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107PubMedCrossRef

Titel: The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes
verfasst von: T. M. Reinbothe
S. Alkayyali
E. Ahlqvist
T. Tuomi
B. Isomaa
V. Lyssenko
E. Renström
Publikationsdatum: 01.02.2013
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 2/2013
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2758-z

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The human L-type calcium channel Ca_v1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

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