title: Otopetrin 1 activation by purinergic nucleotides regulates intracellular calcium.
abstract: Otopetrin1 (Otop1) is a multitransmembrane domain protein required for the formation of otoconia in the vertebrate inner ear. Otoconia are complex calcium carbonate (CaCO(3)) biominerals that are required for the sensation of gravity. Examination of the phenotypes of animals with mutations or deficiencies in Otop1 suggests a direct role for Otop1 in the initiation of extracellular biomineralization, possibly through the regulation of intracellular Ca(2+). Here, we demonstrate that Otop1 overexpression can modulate purinergic-mediated Ca(2+) homeostasis in transfected cell lines. These experiments define a unique set of biochemical activities of Otop1, including depletion of endoplasmic reticulum Ca(2+) stores, specific inhibition of the purinergic receptor P2Y, and regulation of the influx of extracellular Ca(2+) in response to ATP, ADP, and UDP. These activities can be inhibited by the polyanion suramin in a rapidly reversible manner. This first characterization of the consequences of Otop1 overexpression indicates a profound effect on cellular Ca(2+) regulation. In a physiologic setting, these activities could direct the formation and growth of otoconia and regulate other biomineralization processes.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Hughes
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Saito
authors.forename: Paul H
authors.initials: PH
authors.lastname: Schlesinger
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009711:Nucleotides / Q000494:pharmacology*; D012516:Osteosarcoma; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; D009711:Nucleotides; D018048:Receptors, Purinergic P2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D013498:Suramin; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D002118:Calcium; D014544:Uridine Triphosphate