Organelle Selection Determines Agonist-specific Ca2+ Signals in Pancreatic Acinar and β Cells

Abstract

How different extracellular stimuli can evoke different spatiotemporal Ca2؉ signals is uncertain. We have elucidated a novel paradigm whereby different agonists use different Ca 2؉ -storing organelles ("organelle selection") to evoke unique responses. Some agonists select the endoplasmic reticulum (ER), and others select lysosome-related (acidic) organelles, evoking spatial Ca 2؉ responses that mirror the organellar distribution. In pancreatic acinar cells, acetylcholine and bombesin exclusively select the ER Ca 2؉ store, whereas cholecystokinin additionally recruits a lysosome-related organelle. Similarly, in a pancreatic ␤ cell line MIN6, acetylcholine selects only the ER, whereas glucose mobilizes Ca 2؉ from a lysosome-related organelle. We also show that the key to organelle selection is the agonist-specific coupling messenger(s) such that the ER is selected by recruitment of inositol 1,4,5-trisphosphate (or cADP-ribose), whereas lysosome-related organelles are selected by NAADP.

Lysosome-Sarcoplasmic Reticulum Junctions

“…Perhaps most significantly, we provide the first direct evidence in support of the proposal (17,19) that NAADP may selectively elicit Ca 2ϩ signals from a lysosome-related Ca 2ϩ store alone, which may then be amplified by CICR from the SR/ER via RyRs. Furthermore, our data show that NAADP- Red-labeled organelle and ryanodine receptors labeled with BODIPY-ryanodine that co-localize in the same focal plane.…”

“…Previously, we have shown that NAADP induces Ca 2ϩ bursts from a thapsigargin-insensitive store other than the SR and that these local Ca 2ϩ signals are then amplified by subsequent CICR from the SR via RyRs (13). We therefore investigated the possibility that the NAADP-sensitive Ca 2ϩ store in vascular smooth muscle is an acidic, lysosome-related store as previously suggested by investigations on other cell types (17,19).…”

“…The findings of the present investigation are consistent with the idea that a lysosome-related Ca 2ϩ store is the point of origin of NAADP-mediated Ca 2ϩ bursts and suggest that lysosomes may co-localize with RyRs in the SR of arterial smooth muscle cells to form a "trigger zone" for NAADP-dependent Ca 2ϩ signaling. Our data also lend weight to the argument that NAADP-dependent Ca 2ϩ signals may be evoked in a stimulus-specific manner (19), by the potent vasoconstrictor ET-1.…”

“…The aforementioned findings raised the possibility that the spatiotemporal pattern of Ca 2ϩ signals may also be determined via the selection of different intracellular Ca 2ϩ stores in a manner dependent on the nature of the Ca 2ϩ -mobilizing messenger(s) recruited by a given stimulus (15,(17)(18)(19)(20)(21). Further support for this view has recently been provided by the proposal that NAADP triggers Ca 2ϩ release from reserve granules in sea urchin eggs (17), the functional equivalent of lysosomes in mammalian cells.…”

NAADP-mediated Ca 2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist

“…Clearly, in sea urchin eggs, the characterization of NAADP induced Ca 2ϩ release revealed that a receptor/channel different from the InsP 3 receptor or the ryanodine receptor (RyR) is involved (11,18). In addition, Lee's group obtained evidence for a non-ER Ca 2ϩ store sensitive to NAADP in stratified sea urchin eggs (19) that was finally identified as a lysosomal compartment (20)(21)(22)(23). Recent evidence indicates that the novel NAADP receptor on lysosomes is the Ca 2ϩ channel transient receptor potential, mucolipin 1 (TRP-ML1; 24,25).…”