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
DOIs
Publication statusPublished - Sep 17 1996

Keywords

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

ASJC Scopus subject areas

  • General

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