title: Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1 expression and reduced voltage-dependent calcium currents.
abstract: OBJECTIVE
  Type 2 diabetes is characterised by progressive loss of pancreatic beta cell mass and function. Therefore, it is of therapeutic interest to identify factors with the potential to improve beta cell proliferation and insulin secretion. Bone morphogenetic protein 4 (BMP4) expression is increased in diabetic animals and BMP4 reduces glucose-stimulated insulin secretion (GSIS). Here, we investigate the molecular mechanism behind this inhibition.
  
  
  METHODS
  BMP4-mediated inhibition of GSIS was investigated in detail using single cell electrophysiological measurements and live cell Ca(2+) imaging. BMP4-mediated gene expression changes were investigated by microarray profiling, quantitative PCR and western blotting.
  
  
  RESULTS
  Prolonged exposure to BMP4 reduced GSIS from rodent pancreatic islets. This inhibition was associated with decreased exocytosis due to a reduced Ca(2+) current through voltage-dependent Ca(2+) channels. To identify proteins involved in the inhibition of GSIS, we investigated global gene expression changes induced by BMP4 in neonatal rat pancreatic islets. Expression of the Ca(2+)-binding protein calbindin1 was significantly induced by BMP4. Overexpression of calbindin1 in primary islet cells reduced GSIS, and the effect of BMP4 on GSIS was lost in islets from calbindin1 (Calb1) knockout mice.
  
  
  CONCLUSIONS
  We found BMP4 treatment to markedly inhibit GSIS from rodent pancreatic islets in a calbindin1-dependent manner. Calbindin1 is suggested to mediate the effect of BMP4 by buffering Ca(2+) and decreasing Ca(2+) channel activity, resulting in diminished insulin exocytosis. Both BMP4 and calbindin1 are potential pharmacological targets for the treatment of beta cell dysfunction.
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Nørre Alle 20, 2100, Copenhagen, Denmark.
authors.forename: Gitte L
authors.initials: GL
authors.lastname: Christensen
authors.forename: Maria L B
authors.initials: ML
authors.lastname: Jacobsen
authors.forename: Anna
authors.initials: A
authors.lastname: Wendt
authors.forename: Ines G
authors.initials: IG
authors.lastname: Mollet
authors.forename: Josefine
authors.initials: J
authors.lastname: Friberg
authors.forename: Klaus S
authors.initials: KS
authors.lastname: Frederiksen
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.forename: Christine
authors.initials: C
authors.lastname: Bruun
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.forename: Nils
authors.initials: N
authors.lastname: Billestrup
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D064092:Calbindin 1 / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D055724:Electrophysiological Phenomena; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; C576499:Calb1 protein, mouse; C576500:Calb1 protein, rat; D064092:Calbindin 1; C514817:Ins1 protein, mouse; D007328:Insulin; D012333:RNA, Messenger; D002118:Calcium
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