Journal
TRAFFIC
Volume 7, Issue 7, Pages 859-872Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1600-0854.2006.00432.x
Keywords
endoplasmic reticulum; GPN; insulin granules; pancreatic beta-cells; thapsigargin
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Funding
- NIAMS NIH HHS [AR17803] Funding Source: Medline
- NIDDK NIH HHS [DK17047] Funding Source: Medline
- NIGMS NIH HHS [GM72033] Funding Source: Medline
- NINDS NIH HHS [NS27177] Funding Source: Medline
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Many cells show a plateau of elevated cytosolic Ca2+ after a long depolarization, suggesting delayed Ca2+ release from intracellular compartments such as mitochondria and endoplasmic reticulum (ER). Mouse pancreatic beta-cells show a thapsigargin-sensitive plateau ('hump') of Ca2+ after a 30 s depolarization but not after a 10 s depolarization. Surprisingly, this hump depends primarily on compartments other than the mitochondria or ER. It is reduced by only 22% upon blocking mitochondrial Na+-Ca2+ exchange and by only 18% upon blocking ryanodine or IP3 receptors together. Further, the time course of ER Ca2+ measured by a targeted cameleon does not depend on the duration of depolarizations. Instead, the hump is reduced 35% by treatments with the dipeptide glycylphenylalanine beta-napthylamide, a tool often used to lyse lysosomes. We show that this dipeptide does not disturb ER functions, but it lyses acidic compartments and releases Ca2+ into the cytosol. Moreover, it induces leaks in and possibly lyses insulin granules and stops mobilization of secretory granules to the readily releasable pool in beta-cells. We conclude that the dipeptide compromises dense-core secretory granules and that these granules comprise an acidic calcium store in beta-cells whose loading and/or release is sensitive to thapsigargin and which releases Ca2+ after cytosolic Ca2+ elevation.
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