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Inositol 3,4,5,6-tetrakisphosphate inhibits insulin granule acidification and fusogenic potential.

Renström, Erik LU ; Ivarsson, Rosita LU and Shears, Stephen B (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)
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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
ASBMB
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
2007-07-19 08:58:15
date last changed
2017-01-01 04:59:51
@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},
  keyword      = {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    = {ASBMB},
  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},
  volume       = {277},
  year         = {2002},
}