Crosstalk between the cAMP and inositol trisphosphate-signalling pathways in pancreatic beta-cells.
Glucose was found to induce large amplitude oscillations of cytoplasmic Sr2+ and Ca2+ in individual pancreatic beta-cells exposed to the respective cation. Subsequent addition of 20 nM glucagon or other agents raising cAMP triggered pronounced transients superimposed upon the large amplitude oscillations. Hyperpolarization with diazoxide prevented both the large amplitude oscillations and the superimposed transients. After short exposure to carbachol or ATP there was a temporary, and after addition of the Ca2+-ATPase inhibitor thapsigargin a permanent, disappearance of the transients with persistence of the glucose-induced large amplitude oscillations. The Ca2+ channel blocker methoxyverapamil exhibited opposite specificity in preventing the large amplitude oscillations under conditions when the transients often remained. In the presence of methoxyverapamil the transients disappeared during diazoxide hyperpolarization and were restored by subsequent K+ depolarization, which also elevated the content of inositol 1,4,5-trisphosphate (IP3) by 45%. The glucagon-induced transients were obliterated by 12-O-tetradecanoylphorbol 13-acetate, insensitive to ryanodine and paradoxically inhibited by high concentrations of caffeine. The IP3-mediated intracellular ion mobilization induced by carbachol was amplified by glucagon. The results indicate that depolarization-dependent formation of IP3 causes intracellular Ca2+ mobilization in individual beta-cells when the IP3 receptors are sensitized by cAMP. This mechanism may be an important determinant for the electrophysiological burst activity in intact pancreatic islets due to the presence of endogenous glucagon.
Department of Medical Cell Biology, Uppsala University, Biomedicum, Sweden.
Y J
YJ
Liu
E
E
Grapengiesser
E
E
Gylfe
B
B
Hellman
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D005711:Gallopamil / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008820:Mice, Obese; D009991:Oscillometry; D011188:Potassium / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013324:Strontium / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D012433:Ryanodine; D005711:Gallopamil; D002110:Caffeine; D015544:Inositol 1,4,5-Trisphosphate; D005934:Glucagon; D000242:Cyclic AMP; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D003981:Diazoxide; D011188:Potassium; D002118:Calcium; D013324:Strontium