Ca 2 +-induced Ca 2 + Release via Inositol 1,4,5-trisphosphate Receptors Is Amplified by Protein Kinase A and Triggers Exocytosis in Pancreatic β-Cells

• Hormones, such as glucagon and glucagon-like peptide-1, potently amplify nutrient stimulated insulin secretion by raising cAMP. We have studied how cAMP affects Ca 2+ -induced Ca 2+ release (CICR) in pancreatic β-cells from mice and rats and the role of CICR in secretion. CICR was observed as pronounced Ca 2+ spikes on top of glucose- or depolarization-dependent rise of the cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ). cAMP-elevating agents strongly promoted CICR. This effect involved sensitization of the receptors underlying CICR, because many cells exhibited the characteristic Ca 2+ spiking at low or even in the absence of depolarization-dependent elevation of [Ca 2+ ] i . The cAMP effect was mimicked by a specific activator of protein kinase A in cells unresponsive to activators of cAMP-regulated guanine nucleotide exchange factor. Ryanodine pretreatment, which abolishes CICR mediated by ryanodine receptors, did not prevent CICR. Moreover, a high concentration of caffeine, known to activate ryanodine receptors independently of Ca 2+ , failed to mobilize intracellular Ca 2+ . On the contrary, a high caffeine concentration abolished CICR by interfering with inositol 1,4,5-trisphosphate receptors (IP 3 Rs). Therefore, the cell-permeable IP 3 R antagonist 2-aminoethoxydiphenyl borate blocked the cAMP-promoted CICR. Individual CICR events in pancreatic β-cells were followed by [Ca 2+ ] i spikes in neighboring human erythroleukemia cells, used to report secretory events in the β-cells. The results indicate that protein kinase A-mediated promotion of CICR via IP 3 Rs is part of the mechanism by which cAMP amplifies insulin release.

Ämnesord

Medical and Health Sciences  (hsv)

Basic Medicine  (hsv)

Cell and Molecular Biology  (hsv)

Medicin och hälsovetenskap  (hsv)

Medicinska grundvetenskaper  (hsv)

Cell- och molekylärbiologi  (hsv)

Medical and Health Sciences  (hsv)

Basic Medicine  (hsv)

Physiology  (hsv)

Medicin och hälsovetenskap  (hsv)

Medicinska grundvetenskaper  (hsv)

Fysiologi  (hsv)

Medical and Health Sciences  (hsv)

Clinical Medicine  (hsv)

Endocrinology and Diabetes  (hsv)

Medicin och hälsovetenskap  (hsv)

Klinisk medicin  (hsv)

Endokrinologi och diabetes  (hsv)

MEDICINE  (svep)

Morphology, cell biology, pathology  (svep)

Cell biology  (svep)

MEDICIN  (svep)

Morfologi, cellbiologi, patologi  (svep)

Cellbiologi  (svep)

MEDICINE  (svep)

Physiology and pharmacology  (svep)

Physiology  (svep)

MEDICIN  (svep)

Fysiologi och farmakologi  (svep)

Fysiologi  (svep)

MEDICINE  (svep)

Dermatology and venerology,clinical genetics, internal medicine  (svep)

Internal medicine  (svep)

Diabetology  (svep)

MEDICIN  (svep)

Dermatologi och venerologi, klinisk genetik, invärtesmedicin  (svep)

Invärtesmedicin  (svep)

Diabetologi  (svep)

medicinsk cellbiologi  (uu)

Medical Cell Biology  (uu)

Nyckelord

Animals

Calcium/*metabolism

Calcium Channels/*physiology

Cells; Cultured

Cyclic AMP/physiology

Cyclic AMP-Dependent Protein Kinases/*physiology

Exocytosis

Glucagon/pharmacology

Glucagon-Like Peptide 1

Islets of Langerhans/*metabolism

Mice

Mice; Obese

Peptide Fragments/pharmacology

Protein Precursors/pharmacology

Rats

Rats; Wistar

Receptors; Cytoplasmic and Nuclear/*physiology

Research Support; Non-U.S. Gov't

Ryanodine/pharmacology