Inositol 3,4,5,6-tetrakisphosphate inhibits insulin granule acidification and fusogenic potential.
(2002) In Journal of Biological Chemistry 277(30). p.26717-26720- Abstract
- ClC Cl(-) channels in endosomes, synaptosomes, lysosomes, and beta-cell insulin granules provide charge neutralization support for the functionally indispensable acidification of the luminal interior by electrogenic H(+)-ATPases (Jentsch, T. J., Stein, V., Weinreich, F., and Zdebik, A. A. (2002) Physiol. Rev. 82, 503-568). Regulation of ClC activity is, therefore, of widespread biological significance (Forgac, M. (1999) J. Biol. Chem. 274, 12951-12954). We now ascribe just such a regulatory function to the increases in cellular levels of inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P(4)) that inevitably accompany activation of the ubiquitous Ins(1,4,5)P(3) signaling pathway. We used confocal imaging to record insulin granule... (More)
- ClC Cl(-) channels in endosomes, synaptosomes, lysosomes, and beta-cell insulin granules provide charge neutralization support for the functionally indispensable acidification of the luminal interior by electrogenic H(+)-ATPases (Jentsch, T. J., Stein, V., Weinreich, F., and Zdebik, A. A. (2002) Physiol. Rev. 82, 503-568). Regulation of ClC activity is, therefore, of widespread biological significance (Forgac, M. (1999) J. Biol. Chem. 274, 12951-12954). We now ascribe just such a regulatory function to the increases in cellular levels of inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P(4)) that inevitably accompany activation of the ubiquitous Ins(1,4,5)P(3) signaling pathway. We used confocal imaging to record insulin granule acidification in single mouse pancreatic beta-cells. Granule acidification was reduced by perfusion of single cells with 10 microm Ins(3,4,5,6)P(4) (the concentration following receptor activation), whereas at 1 microm ("resting" levels), Ins(3,4,5,6)P(4) was ineffective. This response to Ins(3,4,5,6)P(4) was not mimicked by 100 microm Ins(1,4,5,6)P(4) or by 100 microm Ins(1,3,4,5,6)P(5). Ins(3,4,5,6)P(4) did not affect granular H(+)-ATPase activity or H(+) leak, indicating that Ins(3,4,5,6)P(4) instead inhibited charge neutralization by ClC. The Ins(3,4,5,6)P(4)-mediated inhibition of vesicle acidification reduced exocytic release of insulin as determined by whole-cell capacitance recordings. This may impinge upon type 2 diabetes etiology. Regulatory control over vesicle acidification by this negative signaling pathway in other cell types should be considered. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/109533
- author
- Renström, Erik LU ; Ivarsson, Rosita LU and Shears, Stephen B
- organization
- publishing date
- 2002
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Secretory Vesicles : drug effects, Signal Transduction, Chlorides : metabolism, Non-U.S. Gov't, Support, Cultured, Chloride Channels : metabolism, Animal, Microscopy, Confocal, Islets of Langerhans : metabolism, Mice, Insulin : metabolism, Cells, Inositol Phosphates : pharmacology
- in
- Journal of Biological Chemistry
- volume
- 277
- issue
- 30
- pages
- 26717 - 26720
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000177055900002
- scopus:0037178835
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.C200314200
- language
- English
- LU publication?
- yes
- id
- d0f2ec54-16e6-4cad-8d0a-26ee9884c96e (old id 109533)
- date added to LUP
- 2016-04-01 12:16:23
- date last changed
- 2022-01-27 01:22:56
@article{d0f2ec54-16e6-4cad-8d0a-26ee9884c96e,
abstract = {{ClC Cl(-) channels in endosomes, synaptosomes, lysosomes, and beta-cell insulin granules provide charge neutralization support for the functionally indispensable acidification of the luminal interior by electrogenic H(+)-ATPases (Jentsch, T. J., Stein, V., Weinreich, F., and Zdebik, A. A. (2002) Physiol. Rev. 82, 503-568). Regulation of ClC activity is, therefore, of widespread biological significance (Forgac, M. (1999) J. Biol. Chem. 274, 12951-12954). We now ascribe just such a regulatory function to the increases in cellular levels of inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P(4)) that inevitably accompany activation of the ubiquitous Ins(1,4,5)P(3) signaling pathway. We used confocal imaging to record insulin granule acidification in single mouse pancreatic beta-cells. Granule acidification was reduced by perfusion of single cells with 10 microm Ins(3,4,5,6)P(4) (the concentration following receptor activation), whereas at 1 microm ("resting" levels), Ins(3,4,5,6)P(4) was ineffective. This response to Ins(3,4,5,6)P(4) was not mimicked by 100 microm Ins(1,4,5,6)P(4) or by 100 microm Ins(1,3,4,5,6)P(5). Ins(3,4,5,6)P(4) did not affect granular H(+)-ATPase activity or H(+) leak, indicating that Ins(3,4,5,6)P(4) instead inhibited charge neutralization by ClC. The Ins(3,4,5,6)P(4)-mediated inhibition of vesicle acidification reduced exocytic release of insulin as determined by whole-cell capacitance recordings. This may impinge upon type 2 diabetes etiology. Regulatory control over vesicle acidification by this negative signaling pathway in other cell types should be considered.}},
author = {{Renström, Erik and Ivarsson, Rosita and Shears, Stephen B}},
issn = {{1083-351X}},
keywords = {{Secretory Vesicles : drug effects; Signal Transduction; Chlorides : metabolism; Non-U.S. Gov't; Support; Cultured; Chloride Channels : metabolism; Animal; Microscopy; Confocal; Islets of Langerhans : metabolism; Mice; Insulin : metabolism; Cells; Inositol Phosphates : pharmacology}},
language = {{eng}},
number = {{30}},
pages = {{26717--26720}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Inositol 3,4,5,6-tetrakisphosphate inhibits insulin granule acidification and fusogenic potential.}},
url = {{http://dx.doi.org/10.1074/jbc.C200314200}},
doi = {{10.1074/jbc.C200314200}},
volume = {{277}},
year = {{2002}},
}