A biologic function for an "orphan" messenger: D-myo-inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels.
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 Ca(2+)-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 Ca(2+)-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.
Ismailov
I I
II
Department of Physiology and Biophysics, University of Alabama at Birmingham 35294, USA.
Fuller
C M
CM
Berdiev
B K
BK
Shlyonsky
V G
VG
Benos
D J
DJ
Barrett
K E
KE
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000494:pharmacology; D002147:Calmodulin / Q000494:pharmacology; D002417:Cattle; D018118:Chloride Channels / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D003001:Cloning, Molecular; D004533:Egtazic Acid / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D005260:Female; D007295:Inositol Phosphates / Q000494:pharmacology*; D008051:Lipid Bilayers; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D014982:Xenopus laevis
D002147:Calmodulin; D018118:Chloride Channels; D007295:Inositol Phosphates; D008051:Lipid Bilayers; D011994:Recombinant Proteins; C081652:inositol-3,4,5,6-tetrakisphosphate; D004533:Egtazic Acid; D000255:Adenosine Triphosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium