Human Molecular Genetics Advance Access published online on November 10, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn370
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Cx36 makes channels coupling human pancreatic β - cells, and correlates with insulin expression
1 Surgical Research Unit, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland 2 Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland 3 Department of Cell Physiology and Metabolism, University of Geneva School of Medicine, Geneva, Switzerland 4 Islet Research Laboratory, The Whittier Institute for Diabetes, University of California San Diego, La Jolla, USA 5 Dept Cell Biology, University of Groningen, The Netherlands 6 Department of Endocrinology and Metabolism, University of Pisa, Italy 7 Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA
* Corresponding address: Paolo Meda, MD, Department of Cell Physiology and Metabolism, CMU, 1, rue Michel-Servet, 1211 Geneva 4, CH- Switzerland, E-mail: paolo.meda{at}medecine.unige.ch, Phone: +41 22 379 52 10, Fax number: +41 22 379 52 60
Received September 26, 2008; Revised November 4, 2008; Accepted November 4, 2008
Previous studies have documented that the insulin-producing β-cells of laboratory rodents are coupled by gap junction channels made solely of the connexin36 (Cx36) protein, and have shown that loss of this protein desynchronizes β-cells, leading to secretory defects reminiscent of those observed in type 2 diabetes. Since human islets differ in several respects from those of laboratory rodents, we have now screened human pancreas, and islets isolated thereof, for expression of a variety of connexin genes, tested whether the cognate proteins form functional channels for islet cell exchanges, and assessed whether this expression changes with β-cell function in islets of control and type 2 diabetics. Here, we show that 1) different connexin isoforms are differentially distributed in the exocrine and endocrine parts of the human pancreas, 2) human islets express at the transcript level different connexin isoforms; 3) the membrane of β-cells harbors detectable levels of gap junctions made of Cx36; 4) this protein is concentrated in lipid raft domains of the β-cell membrane where it forms gap junctions; 5) Cx36 channels allow for the preferential exchange of cationic molecules between human β-cells; 6) the levels of Cx36 mRNA correlated with the expression of the insulin gene in the islets of both control and type 2 diabetics. The data show that Cx36 is the native protein of human pancreatic islets that mediates the coupling of the insulin-producing β-cells, and contributes to control β-cell function by modulating gene expression.