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Glucose Regulates Expression of Inositol 1,4,5-Trisphosphate Receptor Isoforms in Isolated Rat Pancreatic Islets¹

Department of Pharmacology and Toxicology (B.L., S.G.L.), School of Medicine and Biomedical Sciences, the State University of New York at Buffalo, Buffalo, New York 14214; and the Research Division (J.-C.J., G.C.W.), Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Dr. Suzanne Laychock, 102 Farber Hall, State University of New York at Buffalo, School of Medicine, Buffalo, New York 14214. E-mail: laychock{at}acsu.buffalo.edu

Isolated rat pancreatic islets were studied to determine the dynamic regulatory effects of glucose stimulation on the expression of messenger RNA (mRNA) and protein levels for inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) isoforms I, II, and III. The relative isoform abundance was: IP3R-III > IP3R-II IP3R-I. Culture of islets with glucose (G; 20 mM) or -ketoisocaproic acid for 30 min increased only IP3R-III mRNA expression above control (5.5 mM glucose). 2-Deoxyglucose was without effect. Islet culture for 2 h with G (20 mM) or -ketoisocaproic acid reduced IP3R-III mRNA expression levels below control, and cycloheximide blocked the response. Culturing islets for 1 day or 7 days with G (11 mM) reduced the expression of IP3R-III mRNA but increased the expression of IP3R-II mRNA in a time-dependent manner. Cytosine arabinoside lowered cultured islet IP3R-II and -III mRNA levels, but glucose effects remained evident. IP3R-II mRNA levels were also significantly higher in islets from hyperglycemic 90% partial pancreatectomized rats, compared with sham animals. Islet IP3R mRNA expression also showed osmotic sensitivity. Islet IP3R-III protein levels increased after 2 h islet culture at 20 mM G, were unchanged after 1 day culture at 11 mM G, and were lower than control after 7 days culture at 11 mM G. In contrast, IP3R-II levels increased after 1 day and 7 days culture at 11 mM G, whereas IP3R-I protein levels remained unchanged. Thus, G stimulation rapidly increases transcription and expression of IP3R-III mRNA and protein levels in rat islets. However, chronic G stimulation up-regulates IP3R-II mRNA in cultured islets and in islets from partial pancreatectomized rats. Metabolic regulation of IP3R-II and III expression may mediate ß-cell IP3-responsive Ca²⁺ mobilization and insulin secretion.

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