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PNAS 104 (29): 12023-12028

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

Otopetrin 1 activation by purinergic nucleotides regulates intracellular calcium

Inna Hughes*, Mitsuyoshi Saito{dagger}, Paul H. Schlesinger{dagger}, and David M. Ornitz*,{ddagger}

Departments of *Molecular Biology and Pharmacology and {dagger}Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110

Communicated by Philip Leder, Harvard Medical School, Boston, MA, June 4, 2007

Received for publication March 15, 2007.

Abstract: Otopetrin1 (Otop1) is a multitransmembrane domain protein required for the formation of otoconia in the vertebrate inner ear. Otoconia are complex calcium carbonate (CaCO3) 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 Ca2+. Here, we demonstrate that Otop1 overexpression can modulate purinergic-mediated Ca2+ homeostasis in transfected cell lines. These experiments define a unique set of biochemical activities of Otop1, including depletion of endoplasmic reticulum Ca2+ stores, specific inhibition of the purinergic receptor P2Y, and regulation of the influx of extracellular Ca2+ 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 Ca2+ regulation. In a physiologic setting, these activities could direct the formation and growth of otoconia and regulate other biomineralization processes.

Key Words: biomineralization • otoconia • purinergic receptor


Author contributions: I.H., M.S., P.H.S., and D.M.O. designed research; I.H. and M.S. performed research; I.H. contributed new reagents/analytic tools; I.H., M.S., P.H.S., and D.M.O. analyzed data; and I.H., P.H.S., and D.M.O. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0705182104/DC1.

{ddagger}To whom correspondence should be addressed. E-mail: dornitz{at}wustl.edu

© 2007 by The National Academy of Sciences of the USA


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