Long-term uncoupling of chloride secretion from intracellular calcium levels by Ins(3,4,5,6)P4.
Osmoregulation, inhibitory neurotransmission and pH balance depend on chloride ion (Cl-) flux. In intestinal epithelial cells, apical Cl- channels control salt and fluid secretion and are, in turn, regulated by agonists acting through cyclic nucleotides and internal calcium ion concentration ([Ca2+]i). Recently, we found that muscarinic pretreatment prevents [Ca2+]i increases from eliciting Cl- secretion in T84 colonic epithelial cells. By studying concomitant inositol phosphate metabolism, we have now identified D-myo-inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4), as the inositol phosphate most likely to mediate this uncoupling. A novel, membrane-permeant ester prepared by total synthesis delivers Ins(3,4,5,6)P4 intracellularly and confirms that this emerging messenger does inhibit Cl- flux resulting from thapsigargin- or histamine-induced [Ca2+]i elevations.
Vajanaphanich
M
M
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla 92093.
Schultz
C
C
Rudolf
M T
MT
Wasserman
M
M
Enyedi
P
P
Craxton
A
A
Shears
S B
SB
Tsien
R Y
RY
Barrett
K E
KE
Traynor-Kaplan
A
A
D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000166:cytology; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D004952:Esters; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism*
D002712:Chlorides; D004952:Esters; D007295:Inositol Phosphates; C081652:inositol-3,4,5,6-tetrakisphosphate; C081651:inositol-1,4,5,6-tetrakisphosphate; D001285:Atropine; D002217:Carbachol; D002118:Calcium