PDF herunterladen
Horm Metab Res 2009; 41(11): 805-813
DOI: 10.1055/s-0029-1225631
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Transcripts of Calcium/Calmodulin-dependent Kinases are Changed After Forskolin- or IBMX-induced Insulin Secretion due to Melatonin Treatment of Rat Insulinoma β-Cells (INS-1)[*]

I. Bazwinsky-Wutschke1 , E. Mühlbauer2 , S. Wolgast2 , E. Peschke1
  • 1Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle, Germany
  • 2Saxon Academy of Sciences Leipzig, Leipzig, Germany
Weitere Informationen

Publikationsverlauf

received 18.03.2009

accepted 04.06.2009

Publikationsdatum:
13. Juli 2009 (online)

Auch verfügbar auf
   Lizenzen und Reprints
Preview

Abstract

The objective of the present study was to examine the effects of melatonin on transcripts of isoforms of calcium/calmodulin-dependent protein kinases in rat insulinoma β-cells INS-1. Investigations show that calcium/calmodulin-dependent kinase IV and calcium/calmodulin-dependent kinase 2d are expressed in human and rat pancreatic islets and INS-1 cells. By application of either forskolin or 3-isobutyl-1-methylxanthine for 6 hours, calcium spiking was evoked and the release of insulin was increased. The expression of the calcium/calmodulin-dependent kinase IV and calcium/calmodulin-dependent kinase 2d transcripts was significantly increased due to forskolin or 3-isobutyl-1-methylxanthine. Acute melatonin treatment (6 h) in the presence of either forskolin or 3-isobutyl-1-methylxanthine caused a significant decrease in insulin release and induced significant downregulation of calcium/calmodulin-dependent kinase IV and calcium/calmodulin-dependent kinase 2d transcripts in INS-1 batch cultures. The attenuating effect of melatonin on transcripts could be almost completely reversed by preincubation with the melatonin receptor antagonist luzindole. Thus, the insulin-inhibiting effect of melatonin in INS-1 cells is associated with significant changes in transcripts of calcium-signaling components suggesting that melatonin influences gene expression of components, which are known to be involved in insulin secretion or insulin gene expression.

Key words

calcium/calmodulin-dependent kinase IV - calcium/calmodulin-dependent kinase 2d - pancreatic islet - insulin secretion

1 Dedicated to Professor Dr. Dr. Bernd Fischer on the occasion of his 60th birthday, August 25th 2009.

Literatur

  • 1 Jones PM, Persaud SJ. Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic β-cells.  Endocr Rev. 1998;  19 429-461
    Suche in Google Scholar
  • 2 Henquin JC, Ravier MA, Nenquin M, Jonas JC, Gilon P. Hierarchy of the beta-cell signals controlling insulin secretion.  Eur J Clin Invest. 2003;  33 742-750
    Suche in Google Scholar
  • 3 Gromada J, Brock B, Schmitz O, Rorsman P. Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential.  Basic Clin Pharmacol Toxicol. 2004;  95 252-262
    Suche in Google Scholar
  • 4 Taskén K, Aandahl EM. Localized effects of cAMP mediated by distinct routes of protein kinase A.  Physiol Rev. 2004;  84 137-167
    Suche in Google Scholar
  • 5 Dyachok O, Sågetorp J, Isakov Y, Tengholm A. cAMP oscillations restrict protein kinase A redistribution in insulin-secreting cells.  Biochem Soc Trans. 2006;  34 498-501
    Suche in Google Scholar
  • 6 Dyachok O, Isakov Y, Sågetorp J, Tengholm A. Oscillations of cyclic AMP in hormone-stimulated insulin-secreting beta-cells.  Nature. 2006;  439 349-352
    Suche in Google Scholar
  • 7 Mellström B, Savignac M, Gomez-Villafuertes R, Naranjo JR. Ca2+-operated transcriptional networks: molecular mechanisms and in vivo models.  Physiol Rev. 2008;  88 421-449
    Suche in Google Scholar
  • 8 Eckert B, Schwaninger M, Knepel W. Calcium-mobilizing insulin secretagogues stimulate transcription that is directed by the cyclic adenosine 3′,5′-monophosphate/calcium response element in a pancreatic islet beta-cell line.  Endocrinology. 1996;  137 225-233
    Suche in Google Scholar
  • 9 Ban N, Yamada Y, Someya Y, Ihara Y, Adachi T, Kubota A, Watanabe R, Kuroe A, Inada A, Miyawaki K, Sunaga Y, Shen ZP, Iwakura T, Tsukiyama K, Toyokuni S, Tsuda K, Seino Y. Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression.  Diabetes. 2000;  49 1142-1148
    Suche in Google Scholar
  • 10 Andrali SS, Sampley ML, Vanderford NL, Ozcan S. Glucose regulation of insulin gene expression in pancreatic beta-cells.  Biochem J. 2008;  415 1-10
    Suche in Google Scholar
  • 11 Niki I, Hidaka H. Roles of intracellular Ca2+-receptors in the pancreatic beta-cell in insulin secretion.  Mol Cell Biochem. 1999;  190 119-124
    Suche in Google Scholar
  • 12 Matsumoto K, Fukunaga K, Miyazaki J, Shichiri M, Miyamoto E. Ca2+/calmodulin-dependent protein kinase II and synapsin I-like protein in mouse insulinoma MIN6 cells.  Endocrinology. 1995;  136 3784-3793
    Suche in Google Scholar
  • 13 Easom RA. CaM kinase II: a protein kinase with extraordinary talents germane to insulin exocytosis.  Diabetes. 1999;  48 675-684
    Suche in Google Scholar
  • 14 Yu X, Murao K, Sayo Y, Imachi H, Cao WM, Ohtsuka S, Niimi M, Tokumitsu H, Inuzuka H, Wong NC, Kobayashi R, Ishida T. The role of calcium/calmodulin-dependent protein kinase cascade in glucose up-regulation of insulin gene expression.  Diabetes. 2004;  53 1475-1481
    Suche in Google Scholar
  • 15 Peschke E, Peschke D. Evidence for a circadian rhythm of insulin release from perifused rat pancreatic islets.  Diabetologia. 1998;  41 1085-1092
    Suche in Google Scholar
  • 16 Peschke E. Melatonin, endocrine pancreas and diabetes.  J Pineal Res. 2008;  44 26-40
    Suche in Google Scholar
  • 17 Peschke E, Mühlbauer E, Musshoff U, Csernus VJ, Chankiewitz E, Peschke D. Receptor MT1 mediated influence of melatonin on cAMP concentration and insulin secretion of rat insulinoma cells INS-1.  J Pineal Res. 2002;  33 63-71
    Suche in Google Scholar
  • 18 Peschke E, Peschke D, Hammer T, Csernus VJ. Influence of melatonin and serotonin on glucose-stimulated insulin release from perifused rat pancreatic islets in vitro.  J Pineal Res. 1997;  23 156-163
    Suche in Google Scholar
  • 19 Peschke E, Fauteck JD, Musshoff U, Schmidt F, Beckmann A, Peschke D. Evidence for a melatonin receptor within pancreatic islets of neonate rats: functional, autoradiographic, and molecular investigations.  J Pineal Res. 2000;  28 156-164
    Suche in Google Scholar
  • 20 Peschke E, Bach AG, Mühlbauer E. Parallel signaling pathways of melatonin in the pancreatic beta-cell.  J Pineal Res. 2006;  40 184-191
    Suche in Google Scholar
  • 21 Laychock SG. Impaired cyclic AMP response to stimuli in glucose-desensitized rat pancreatic islets.  Mol Cell Endocrinology. 1995;  113 19-28
    Suche in Google Scholar
  • 22 Stumpf I, Mühlbauer E, Peschke E. Involvement of the cGMP pathway in mediating the insulin-inhibitory effect of melatonin in pancreatic beta-cells.  J Pineal Res. 2008;  45 318-327
    Suche in Google Scholar
  • 23 Mühlbauer E, Peschke E. Evidence for the expression of both the MT1- and in addition, the MT2-melatonin receptor, in the rat pancreas, islet and beta-cell.  J Pineal Res. 2007;  42 105-106
    Suche in Google Scholar
  • 24 Peschke E, Stumpf I, Bazwinsky I, Litvak L, Dralle H, Mühlbauer E. Melatonin and type 2 diabetes – a possible link?.  J Pineal Res. 2007;  42 350-358
    Suche in Google Scholar
  • 25 Csernus VJ, Hammer T, Peschke D, Peschke E. Dynamic insulin secretion from perifused rat pancreatic islets.  Cell Mol Life Sci. 1998;  54 733-743
    Suche in Google Scholar
  • 26 Mühlbauer E, Wolgast S, Finckh U, Peschke D, Peschke E. Indication of circadian oscillations in the rat pancreas.  FEBS Lett. 2004;  564 91-96
    Suche in Google Scholar
  • 27 Pfaffl MW, Horgan GW, Dempfle L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR.  Nucleic Acids Res. 2002;  30 e36
    Suche in Google Scholar
  • 28 Bach AG, Wolgast S, Mühlbauer E, Peschke E. Melatonin stimulates inositol-1,4,5-trisphosphate and Ca2+ release from INS-1 insulinoma cells.  J Pineal Res. 2005;  39 316-323
    Suche in Google Scholar
  • 29 Mühlbauer E, Bazwinsky I, Wolgast S, Klemenz A, Peschke E. Circadian changes of ether-a-go-go-related-gene (Erg) potassium channel transcripts in the rat pancreas and beta-cell.  Cell Mol Life Sci. 2007;  64 768-780
    Suche in Google Scholar
  • 30 Shafer SH, Phelps SH, Williams CL. Reduced DNA synthesis and cell viability in small cell lung carcinoma by treatment with cyclic AMP phosphodiesterase inhibitors.  Biochem Pharmacol. 1998;  56 1229-1236
    Suche in Google Scholar
  • 31 Hanoune J, Defer N. Regulation and role of adenylyl cyclase isoforms.  Annu Rev Pharmacol Toxicol. 2001;  41 145-174
    Suche in Google Scholar
  • 32 Kemp DM, Ubeda M, Habener JF. Identification and functional characterization of melatonin Mel1a receptors in pancreatic beta cells: potential role in incretin-mediated cell function by sensitization of cAMP signaling.  Mol Cell Endocrinol. 2002;  191 157-166
    Suche in Google Scholar
  • 33 Godson C, Reppert SM. The Mel1a melatonin receptor is coupled to parallel signal transduction pathways.  Endocrinology. 1997;  138 397-404
    Suche in Google Scholar
  • 34 Witt-Enderby PA, Masana MI, Dubocovich ML. Physiological exposure to melatonin supersensitizes the cyclic adenosine 3′,5′-monophosphate-dependent signal transduction cascade in Chinese hamster ovary cells expressing the human mt1 melatonin receptor.  Endocrinology. 1998;  139 3064-3071
    Suche in Google Scholar
  • 35 Picinato MC, Haber EP, Cipolla-Neto J, Curi R, de Oliveira Carvalho CR, Carpinelli AR. Melatonin inhibits insulin secretion and decreases PKA levels without interfering with glucose metabolism in rat pancreatic islets.  J Pineal Res. 2002;  33 156-160
    Suche in Google Scholar
  • 36 Usachev Y, Verkhratsky A. IBMX induces calcium release from intracellular stores in rat sensory neurones.  Cell Calcium. 1995;  17 197-206
    Suche in Google Scholar
  • 37 Usachev Y, Kostyuk P, Verkhratsky A. 3-Isobutyl-1-methylxanthine (IBMX) affects potassium permeability in rat sensory neurones via pathways that are sensitive and insensitive to [Ca2+]in.  Pflugers Arch. 1995;  430 420-428
    Suche in Google Scholar
  • 38 Dolphin AC, Forda SR, Scott RH. Calcium-dependent currents in cultured rat dorsal root ganglion neurones are inhibited by an adenosine analogue.  J Physiol. 1986;  373 47-61
    Suche in Google Scholar
  • 39 Choi OH, Shamim MT, Padgett WL, Daly JW. Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors.  Life Sci. 1988;  43 387-398
    Suche in Google Scholar
  • 40 Fearon IM, Palmer AC, Balmforth AJ, Ball SG, Mikala G, Peers C. Inhibition of recombinant human cardiac L-type Ca2+ channel alpha1C subunits by 3-isobutyl-1-methylxanthine.  Eur J Pharmacol. 1998;  342 353-358
    Suche in Google Scholar
  • 41 Jockers R, Maurice P, Boutin JA, Delagrange P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new?.  Br J Pharmacol. 2008;  154 1182-1195
    Suche in Google Scholar
  • 42 Dubocovich ML, Yun K, Al-Ghoul WM, Benloucif S, Masana MI. Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms.  FASEB J. 1998;  12 1211-1220
    Suche in Google Scholar
  • 43 Browning C, Beresford I, Fraser N, Giles H. Pharmacological characterization of human recombinant melatonin MT(1) and MT(2) receptors.  Br J Pharmacol. 2000;  129 877-886
    Suche in Google Scholar
  • 44 Ayoub MA, Levoye A, Delagrang EP, Jockers R. Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers.  Mol Pharmacol. 2004;  66 312-321
    Suche in Google Scholar
  • 45 Suzuki Y, Zhang H, Saito N, Kojima I, Urano T, Mogami H. Glucagon-like peptide 1 activates protein kinase C through Ca2+-dependent activation of phospholipase C in insulin-secreting cells.  J Biol Chem. 2006;  281 28499-28507
    Suche in Google Scholar
  • 46 Baltrusch S, Lenzen S. Regulation of [Ca2+]i oscillations in mouse pancreatic islets by adrenergic agonists.  Biochem Biophys Res Commun. 2007;  363 1038-1043
    Suche in Google Scholar
  • 47 Chaloux B, Caron AZ, Guillemette G. Protein kinase A increases the binding affinity and the Ca2+ release activity of the inositol 1,4,5-trisphosphate receptor type 3 in RINm5F cells.  Biol Cell. 2007;  99 379-388
    Suche in Google Scholar
  • 48 Landa Jr LR, Harbeck M, Kaihara K, Chepurny O, Kitiphongspattana K, Graf O, Nikolaev VO, Lohse MJ, Holz GG, Roe MW. Interplay of Ca2+ and cAMP signaling in the insulin-secreting MIN6 beta-cell line.  J Biol Chem. 2005;  280 31294-31302
    Suche in Google Scholar
  • 49 Slanar O, Pelisek V, Vanecek J. Melatonin inhibits pituitary adenylyl cyclase-activating polypeptide-induced increase in cyclic AMP accumulation and [Ca2+]i in cultured cells of neonatal rat pituitary.  Neurochem Int. 2000;  36 213-219
    Suche in Google Scholar
  • 50 Vanecek J. Inhibitory effect of melatonin on GnRH-induced LH release.  Rev Reprod. 1999;  4 67-72
    Suche in Google Scholar
  • 51 Dai J, Inscho EW, Yuan L, Hill SM. Modulation of intracellular calcium and calmodulin by melatonin in MCF-7 human breast cancer cells.  J Pineal Res. 2002;  32 112-119
    Suche in Google Scholar
  • 52 Schuster C, Williams LM, Morris A, Morgan PJ, Barrett P. The human MT1 melatonin receptor stimulates cAMP production in the human neuroblastoma cell line SH-SY5Y cells via a calcium-calmodulin signal transduction pathway.  J Neuroendocrinol. 2005;  1 170-178
    Suche in Google Scholar
  • 53 Benítez-King G, Ríos A, Martínez A, Antón-Tay F. In vitro inhibition of Ca2+ calmodulin-dependent kinase II activity by melatonin.  Biochim Biophys Acta. 1996;  1290 191-196
    Suche in Google Scholar
  • 54 Fukunaga K, Horikawa K, Shibata S, Takeuchi Y, Miyamoto E. Ca2+/calmodulin-dependent protein kinase II-dependent long-term potentiation in the rat suprachiasmatic nucleus and its inhibition by melatonin.  J Neurosci Res. 2002;  70 799-807
    Suche in Google Scholar
  • 55 Daniel PB, Walker WH, Habener JF. Cyclic AMP signaling and gene regulation.  Ann Rev Nutr. 1998;  18 353-383
    Suche in Google Scholar
  • 56 McNulty S, Ross AW, Barrett P, Hastings MH, Morgan PJ. Melatonin regulates the phosphorylation of CREB in ovine pars tuberalis.  J Neuroendocrinol. 1994;  6 523-532
    Suche in Google Scholar
  • 57 McNulty S, Ross AW, Shiu KY, Morgan PJ, Hastings MH. Phosphorylation of CREB in ovine pars tuberalis is regulated both by cyclic AMP-dependent and cyclic AMP-independent mechanisms.  J Neuroendocrinol. 1996;  8 635-645
    Suche in Google Scholar
  • 58 McNulty S, Schurov IL, Sloper PJ, Hasting MH. Stimuli which entrain the circadian clock of the neonatal Syrian hamster in vivo regulate the phosphorylation of the transcription factor CREB in the suprachiasmatic nucleus in vitro.  Eur J Neurosci. 1998;  10 1063-1072
    Suche in Google Scholar
  • 59 von Gall C, Weaver DR, Kock M, Korf HW, Stehle JH. Melatonin limits transcriptional impact of phosphoCREB in the mouse SCN via the Mel1a receptor.  Neuroreport. 2000;  11 1803-1807
    Suche in Google Scholar
  • 60 Sheynzon P, Korf HW. Targeted deletions of Mel1a and Mel1b melatonin receptors affect pCREB levels in lactotroph and pars intermedia cells of mice.  Neurosci Lett. 2006;  407 48-52
    Suche in Google Scholar
  • 61 Tabuchi H, Yamamoto H, Matsumoto K, Ebihara K, Takeuchi Y, Fukunaga K, Hiraoka H, Sasaki Y, Shichiri M, Miyamoto E. Regulation of insulin secretion by overexpression of Ca2+/calmodulin-dependent protein kinase II in insulinoma MIN6 cells.  Endocrinology. 2000;  141 2350-2360
    Suche in Google Scholar
  • 62 Osterhoff M, Möhlig M, Schwanstecher M, Seufert J, Ortmann J, Schatz H, Pfeiffer AF. Ca2+/calmodulin-dependent protein kinase II delta2 regulates gene expression of insulin in INS-1 rat insulinoma cells.  Cell Calcium. 2003;  33 175-184
    Suche in Google Scholar

1 Dedicated to Professor Dr. Dr. Bernd Fischer on the occasion of his 60th birthday, August 25th 2009.

Correspondence

Dr. I. Bazwinsky-Wutschke

Institute of Anatomy and Cell Biology

Martin Luther University Halle-Wittenberg

Grosse Steinstrasse 52

06097 Halle

Germany

Telefon: +49/34/5557 17 10

Fax: +49/34/5557 40 53

eMail: ivonne.bazwinsky@medizin.uni-halle.de