Long-term uncoupling of chloride secretion from intracellular calcium levels by lns(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 ([Ca^{2 +}]_i)^1-3. Recently, we found that muscarinic pretreatment prevents [Ca^{2 +}]_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 [Ca^{2 +}]_i elevations.