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Hearing New Things About Calcium

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Science  03 Aug 2007:
Vol. 317, Issue 5838, pp. 573
DOI: 10.1126/science.317.5838.573c

Otoconia, particles in the inner ear composed of a proteinaceous core coated with CaCO3 crystals, underlie our sense of balance. Otoconial development depends on otopetrin 1 (Otop1), a member of a protein family defined by a highly conserved transmembrane domain of unknown function. Its predicted structure, together with its extracellular location, suggested to Hughes et al. that Otop1 was likely to associate with globular substance vesicles that have previously been shown to respond to ATP with an increase in intravesicular Ca2+. When overexpressed in COS7 cells, Otop1 abolished an early peak in intracellular Ca2+ concentration that was elicited in wild-type cells by extracellular ATP or UTP. Both nucleotides activate P2Y purinergic receptors, which signal through the Gαq family of heterotrimeric guanine nucleotide-binding proteins. Signaling through other Gαq-coupled receptors was maintained in the presence of Otop1, suggesting that the Otop1-mediated decrease in endoplasmic reticulum Ca2+ stores was not sufficient to abolish all rapid Gαq-dependent Ca2+ signals and that P2Y inhibition occurred upstream of Gαq. ATP also elicited a slower sustained phase of increased intracellular Ca2+ (a Ca2+ plateau), yet cells overexpressing Otop1 exhibited a Ca2+ plateau even after treatment with thapsigargin. The effects of Otop1 on the Ca2+ response to ATP were reversibly inhibited by suramin (which inhibits the ATP-dependent Ca2+ response of globular substance vesicles), and the authors conclude that Otop1 has marked effects on the Ca2+ response to ATP that could be critical to its role in otoconia formation. — EMA

Proc. Natl. Acad. Sci. U.S.A. 104, 12023 (2007).

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