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Regulation of Inositol Trisphosphate Receptor Isoform Expression in Glucose-Desensitized Rat Pancreatic Islets: Role of Cyclic Adenosine 3',5'-Monophosphate and Calcium¹

Department of Pharmacology and Toxicology, State University of New York, School of Medicine and Biomedical Sciences, Buffalo, New York 14214

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

The regulation of inositol 1,4,5-trisphosphate receptor (IP3R) messenger RNA (mRNA) and protein expression was investigated in glucose-desensitized rat isolated pancreatic islets. Islets were cultured for 4 days with glucose (11 mM; G-treated) to induce desensitization; IP3R-I mRNA levels were similar to basal (5.5 mM glucose) values, whereas IP3R-II mRNA levels were increased and IP3R-III levels were reduced compared with basal levels. Somatostatin increased the expression of IP3R-II mRNA and reduced the expression of IP3R-III mRNA compared with basal values, but did not significantly affect G-treated islet IP3R expression. When forskolin (FSK), 8-bromo-cAMP, and glucagon-like peptide 1-(7–36) amide were added to G-treated islets after 4 days of culture, IP3R-II mRNA levels were reduced, whereas IP3R-III mRNA levels increased, to levels observed in control islets, within 3 h. The levels of IP3R-I mRNA were unaffected by either somatostatin or FSK. The protein kinase A inhibitor, H-89, and actinomycin D prevented the effects of FSK. A Ca²⁺ ionophore mimicked the effects of FSK on IP3R mRNA expression, whereas blockade of voltage-dependent Ca²⁺ channels or chelation of intracellular Ca²⁺ inhibited the actions of FSK. cAMP also increased IP3R-III mRNA in insulinoma cells. In G-treated islets, FSK slowed IP3R-III mRNA degradation. FSK, but not glucose, stimulated protein kinase A activation in G-treated islets. Thus, cAMP mediates changes in IP3R-II and -III mRNA transcription and stability in glucose-desensitized islets. The regulated expression of IP3R-II and -III mRNA is mediated in part by intracellular Ca²⁺ availability.

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