title: Long-term uncoupling of chloride secretion from intracellular calcium levels by Ins(3,4,5,6)P4.
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). 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.
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, La Jolla 92093.
authors.forename: M
authors.initials: M
authors.lastname: Vajanaphanich
authors.forename: C
authors.initials: C
authors.lastname: Schultz
authors.forename: M T
authors.initials: MT
authors.lastname: Rudolf
authors.forename: M
authors.initials: M
authors.lastname: Wasserman
authors.forename: P
authors.initials: P
authors.lastname: Enyedi
authors.forename: A
authors.initials: A
authors.lastname: Craxton
authors.forename: S B
authors.initials: SB
authors.lastname: Shears
authors.forename: R Y
authors.initials: RY
authors.lastname: Tsien
authors.forename: K E
authors.initials: KE
authors.lastname: Barrett
authors.forename: A
authors.initials: A
authors.lastname: Traynor-Kaplan
mesh_terms: 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*
chemical_list: 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