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 (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.