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)1-3. Recently, we found that muscarinic pretreatment prevents [Ca2 +]i increases from eliciting Cl- secretion in T84 colonic epithelial cells4. 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 messenger5 does inhibit Cl- flux resulting from thapsigargin- or histamine-induced [Ca2 +]i elevations.
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