Abstract
Among many cellular functions, inositol pyrophosphates (PP-InsPs) are metabolic messengers involved in the regulation of glucose uptake, insulin sensitivity, and weight gain. However, their mechanisms of action are still poorly understood. So far, the influence of PP-InsPs on cellular metabolism has been studied by overexpression or knockout/inhibition of relevant metabolizing kinases (IP6Ks, PPIP5Ks). These approaches are, inter alia, limited by time-resolution and potential compensation mechanisms. Here, we describe the synthesis of cell-permeant caged PP-InsPs as tools to rapidly modulate intracellular levels of defined isomers of PP-InsPs in a genetically non-perturbed cellular environment. We show that caged prometabolites readily enter live cells where they are enzymatically converted into still inactive, metabolically stable, photocaged PP-InsPs. Upon light-triggered release of 5-PP-InsP 5 , the major cellular inositol pyrophosphate, oscillations of intracellular Ca 2+ levels in MIN6 cells were transiently reduced to spontaneously recover again. In contrast, uncaging of 1-PP-InsP 5 , a minor cellular isomer, was without effect. These results provide evidence that PP-InsPs play an active role in regulating [Ca 2+ ] i oscillations, a key element in triggering exocytosis and secretion in β-cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2687-2692 |
| Number of pages | 6 |
| Journal | Chemical Science |
| Volume | 10 |
| Issue number | 9 |
| DOIs | |
| State | Published - Jan 1 2019 |
Fingerprint
ASJC Scopus subject areas
- Chemistry(all)
Cite this
Photolysis of cell-permeant caged inositol pyrophosphates controls oscillations of cytosolic calcium in a β-cell line. / Hauke, S.; Dutta, A. K.; Eisenbeis, V. B.; Bezold, D.; Bittner, T.; Wittwer, C.; Thakor, D.; Pavlovic, I.; Schultz, Carsten; Jessen, H. J.
In: Chemical Science, Vol. 10, No. 9, 01.01.2019, p. 2687-2692.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Photolysis of cell-permeant caged inositol pyrophosphates controls oscillations of cytosolic calcium in a β-cell line
AU - Hauke, S.
AU - Dutta, A. K.
AU - Eisenbeis, V. B.
AU - Bezold, D.
AU - Bittner, T.
AU - Wittwer, C.
AU - Thakor, D.
AU - Pavlovic, I.
AU - Schultz, Carsten
AU - Jessen, H. J.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Among many cellular functions, inositol pyrophosphates (PP-InsPs) are metabolic messengers involved in the regulation of glucose uptake, insulin sensitivity, and weight gain. However, their mechanisms of action are still poorly understood. So far, the influence of PP-InsPs on cellular metabolism has been studied by overexpression or knockout/inhibition of relevant metabolizing kinases (IP6Ks, PPIP5Ks). These approaches are, inter alia, limited by time-resolution and potential compensation mechanisms. Here, we describe the synthesis of cell-permeant caged PP-InsPs as tools to rapidly modulate intracellular levels of defined isomers of PP-InsPs in a genetically non-perturbed cellular environment. We show that caged prometabolites readily enter live cells where they are enzymatically converted into still inactive, metabolically stable, photocaged PP-InsPs. Upon light-triggered release of 5-PP-InsP 5 , the major cellular inositol pyrophosphate, oscillations of intracellular Ca 2+ levels in MIN6 cells were transiently reduced to spontaneously recover again. In contrast, uncaging of 1-PP-InsP 5 , a minor cellular isomer, was without effect. These results provide evidence that PP-InsPs play an active role in regulating [Ca 2+ ] i oscillations, a key element in triggering exocytosis and secretion in β-cells.
AB - Among many cellular functions, inositol pyrophosphates (PP-InsPs) are metabolic messengers involved in the regulation of glucose uptake, insulin sensitivity, and weight gain. However, their mechanisms of action are still poorly understood. So far, the influence of PP-InsPs on cellular metabolism has been studied by overexpression or knockout/inhibition of relevant metabolizing kinases (IP6Ks, PPIP5Ks). These approaches are, inter alia, limited by time-resolution and potential compensation mechanisms. Here, we describe the synthesis of cell-permeant caged PP-InsPs as tools to rapidly modulate intracellular levels of defined isomers of PP-InsPs in a genetically non-perturbed cellular environment. We show that caged prometabolites readily enter live cells where they are enzymatically converted into still inactive, metabolically stable, photocaged PP-InsPs. Upon light-triggered release of 5-PP-InsP 5 , the major cellular inositol pyrophosphate, oscillations of intracellular Ca 2+ levels in MIN6 cells were transiently reduced to spontaneously recover again. In contrast, uncaging of 1-PP-InsP 5 , a minor cellular isomer, was without effect. These results provide evidence that PP-InsPs play an active role in regulating [Ca 2+ ] i oscillations, a key element in triggering exocytosis and secretion in β-cells.
UR - http://www.scopus.com/inward/record.url?scp=85062214208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062214208&partnerID=8YFLogxK
U2 - 10.1039/c8sc03479f
DO - 10.1039/c8sc03479f
M3 - Article
AN - SCOPUS:85062214208
VL - 10
SP - 2687
EP - 2692
JO - Chemical Science
JF - Chemical Science
SN - 2041-6520
IS - 9
ER -