Otopetrin 1 activation by purinergic nucleotides regulates intracellular calcium

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 bionnineralization, 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 bionnineralization processes.