The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation.
Defective glucose-stimulated insulin secretion is the main cause of hyperglycemia in type 2 diabetes mellitus. Mutations in HNF-1alpha cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion. Here we report that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1alpha in pancreatic beta cells. Expression of collectrin was decreased in the islets of HNF-1alpha (-/-) mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in rat insulinoma INS-1 cells or in the beta cells of transgenic mice enhanced glucose-stimulated insulin exocytosis, without affecting Ca(2+) influx. Conversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP-25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.
Fukui
Kenji
K
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita Osaka 565-0871, Japan.
Yang
Qin
Q
Cao
Yang
Y
Takahashi
Noriko
N
Hatakeyama
Hiroyasu
H
Wang
Haiyan
H
Wada
Jun
J
Zhang
Yanling
Y
Marselli
Lorella
L
Nammo
Takao
T
Yoneda
Kazue
K
Onishi
Mineki
M
Higashiyama
Shigeki
S
Matsuzawa
Yuji
Y
Gonzalez
Frank J
FJ
Weir
Gordon C
GC
Kasai
Haruo
H
Shimomura
Iichiro
I
Miyagawa
Jun-ichiro
J
Wollheim
Claes B
CB
Yamagata
Kazuya
K
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005089:Exocytosis; D017930:Genes, Reporter; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D051537:Hepatocyte Nuclear Factor 1 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007340:Insulinoma; D007515:Islets of Langerhans / Q000166:cytology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000378:metabolism; D017785:Photons; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050600:SNARE Proteins / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
C429534:CLTRN protein, human; D018076:DNA, Complementary; D007328:Insulin; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050600:SNARE Proteins; D051537:Hepatocyte Nuclear Factor 1; D013006:Growth Hormone; D005982:Glutathione Transferase; D005947:Glucose; D002118:Calcium