title: Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent signal for insulin secretion.
abstract: The ryanodine (RY) receptors in beta-cells amplify signals by Ca2+-induced Ca2+ release (CICR). The role of CICR in insulin secretion remains unclear in spite of the fact that caffeine is known to stimulate secretion. This effect of caffeine is attributed solely to the inhibition of cAMP-phosphodiesterases (cAMP-PDEs). We demonstrate that stimulation of insulin secretion by caffeine is due to a sensitization of the RY receptors. The dose-response relationship of caffeine-induced inhibition of cAMP-PDEs was not correlated with the stimulation of insulin secretion. Sensitization of the RY receptors stimulated insulin secretion in a context-dependent manner, that is, only in the presence of a high concentration of glucose. This effect of caffeine depended on an increase in [Ca2+]i. Confocal images of beta-cells demonstrated an increase in [Ca2+]i induced by caffeine but not by forskolin. 9-Methyl-7-bromoeudistomin D (MBED), which sensitizes RY receptors, did not inhibit cAMP-PDEs, but it stimulated secretion in a glucose-dependent manner. The stimulation of secretion by caffeine and MBED involved both the first and the second phases of secretion. We conclude that the RY receptors of beta-cells mediate a distinct glucose-dependent signal for insulin secretion and may be a target for developing drugs that will stimulate insulin secretion only in a glucose-dependent manner.
authors.affiliation: Department of Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bruton
authors.forename: Raf
authors.initials: R
authors.lastname: Lemmens
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Shi
authors.forename: Solveig
authors.initials: S
authors.lastname: Persson-Sjögren
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
authors.forename: Masroor
authors.initials: M
authors.lastname: Ahmed
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.forename: Mhairi
authors.initials: M
authors.lastname: Frame
authors.forename: Brian L
authors.initials: BL
authors.lastname: Furman
authors.forename: Md Shahidul
authors.initials: MS
authors.lastname: Islam
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D002243:Carbolines; D007328:Insulin; D019837:Ryanodine Receptor Calcium Release Channel; C060741:9-methyl-7-bromoeudistomin D; D002110:Caffeine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D005947:Glucose; D002118:Calcium