Long-term uncoupling of chloride secretion from intracellular calcium levels by lns(3,4,5,6)P4

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Abstract
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.