Otopetrin 1 activation by purinergic nucleotides regulates intracellular calcium

摘要

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.