Ryanodine receptors in human pancreatic β cells: localization and effects on insulin secretion

ABSTRACT It is clear that pancreatic β‐cell dysfunction, including basal hyperinsulinemia and reduced insulin release in response to glucose, is a key determinant of disease progression in type 2 diabetes, but the underlying molecular defects are not known. In diabetes, the expression and function o...

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Veröffentlicht in:The FASEB journal 2004-05, Vol.18 (7), p.878-880
Hauptverfasser: Johnson, James D., Kuang, Shihuan, Misler, Stanley, Polonsky, Kenneth S.
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Sprache:eng
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Zusammenfassung:ABSTRACT It is clear that pancreatic β‐cell dysfunction, including basal hyperinsulinemia and reduced insulin release in response to glucose, is a key determinant of disease progression in type 2 diabetes, but the underlying molecular defects are not known. In diabetes, the expression and function of ryanodine receptor (RyR) Ca2+ release channels are reduced. The present studies were undertaken to define the subcellular location and role of RyR in the control of stimulated and basal insulin release from human pancreatic β cells. Using confocal microscopy, we observed RyR immunoreactivity in a vesicular pattern. RyRs did not colocalize with insulin secretory granules but partially colocalized with endosomes. Direct activation with nanomolar concentrations of ryanodine evoked increases in cytosolic Ca2+ that were coupled to transient insulin release. Insulin release stimulated by 1 nM ryanodine was sensitive to BAPTA‐AM preincubation but independent of thapsigargin‐sensitive endoplasmic reticulum (ER) Ca2+ pools. Blocking RyRs with micromolar concentrations of ryanodine led to BAPTA‐resistant insulin release that was not associated with an increase in cytosolic Ca2+, which implicated alterations in luminal Ca2+. However, neither Ca2+ signals nor insulin release stimulated by glucose was blocked by 10–50 µM ryanodine, which suggests that the CD38/cyclic ADP‐ribose/RyR pathway is not a primary mechanism of glucose action in nontransformed β cells. We provide the first evidence that RyRs directly control insulin secretion in primary β cells. Unexpectedly, stimulation of insulin secretion by ryanodine occurs independently of glucose and by two mechanisms, including a novel cytosolic Ca2+‐independent mechanism likely involving changes in Ca2+ within the lumens of non‐ER organelles, such as endosomes.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.03-1280fje