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 [Elektronisk resurs]

• 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. 

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Cell- och molekylärbiologi  (hsv)

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Klinisk medicin  (hsv)

Endokrinologi och diabetes  (hsv)

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Morphology, cell biology, pathology  (svep)

Cell biology  (svep)

MEDICIN  (svep)

Morfologi, cellbiologi, patologi  (svep)

Cellbiologi  (svep)

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Physiology  (svep)

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Indexterm och SAB-rubrik

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