A biologic function for an "orphan" messenger

D-myo-Inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels

Iskander I. Ismailov, Catherine M. Fuller, Bakhram K. Berdiev, Vadim G. Shlyonsky, Dale J. Benos, Kim E. Barrett

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Inositol phosphates are a family of water-soluble intracellular signaling molecules derived from membrane inositol phospholipids. They undergo a variety of complex interconversion pathways, and their levels are dynamically regulated within the cytosol in response to a variety of agonists. Relatively little is known about the biological function of most members of this family, with the exception of inositol 1,4,5-trisphosphate. Specifically, the biological functions of inositol tetrakisphosphates are largely obscure. In this paper, we report that D-myo-inositol 3,4,5,6-tetrakisphosphate (D-Ins(3,4,5,6)P4) has a direct biphasic (activation/ inhibition) effect on an epithelial Ca2+-activated chloride channel. The effect of D-Ins(3,4,5,6)P4 is not mimicked by other inositol tetrakisphosphate isomers, is dependent on the prevailing calcium concentration, and is influenced when channels are phosphorylated by calmodulin kinase II. The predominant effect of D-Ins(3,4,5,6)P4 on phosphorylated channels is inhibitory at levels of intracellular calcium observed in stimulated cells. Our findings indicate the biological function of a molecule hitherto considered as an "orphan" messenger. They suggest that the molecular target for D-Ins(3,4,5,6)P4 is a plasma membrane Ca2+-activated chloride channel. Regulation of this channel by D-Ins(3,4,5,6)P4 and Ca2+ may have therapeutic implications for the disease states of both diabetic nephropathy and cystic fibrosis.

Original languageEnglish
Pages (from-to)10505-10509
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number19
Publication statusPublished - Sep 17 1996
Externally publishedYes

Fingerprint

Chloride Channels
Orphaned Children
Inositol
Calcium
Calcium-Calmodulin-Dependent Protein Kinases
Inositol 1,4,5-Trisphosphate
Inositol Phosphates
Diabetic Nephropathies
Phosphatidylinositols
Cystic Fibrosis
Cytosol
Cell Membrane
inositol-3,4,5,6-tetrakisphosphate
D-myo-inositol 3,4,5,6-tetrakisphosphate
Membranes
Water

Keywords

  • Chloride transport
  • Cystic fibrosis
  • Inositol phosphates
  • Signal transduction

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

A biologic function for an "orphan" messenger : D-myo-Inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels. / Ismailov, Iskander I.; Fuller, Catherine M.; Berdiev, Bakhram K.; Shlyonsky, Vadim G.; Benos, Dale J.; Barrett, Kim E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 19, 17.09.1996, p. 10505-10509.

Research output: Contribution to journalArticle

Ismailov, Iskander I. ; Fuller, Catherine M. ; Berdiev, Bakhram K. ; Shlyonsky, Vadim G. ; Benos, Dale J. ; Barrett, Kim E. / A biologic function for an "orphan" messenger : D-myo-Inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels. In: Proceedings of the National Academy of Sciences of the United States of America. 1996 ; Vol. 93, No. 19. pp. 10505-10509.
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