Regulation of cellular calcium in vestibular supporting cells by otopetrin 1.
Otopetrin 1 (OTOP1) is a multitransmembrane domain protein, which is essential for mineralization of otoconia, the calcium carbonate biominerals required for vestibular function, and the normal sensation of gravity. The mechanism driving mineralization of otoconia is poorly understood, but it has been proposed that supporting cells and a mechanism to maintain high concentrations of calcium are critical. Using Otop1 knockout mice and a utricular epithelial organ culture system, we show that OTOP1 is expressed at the apex of supporting cells and functions to increase cytosolic calcium in response to purinergic agonists, such as adenosine 5'-triphosphate (ATP). This is achieved by blocking mobilization of calcium from intracellular stores in an extracellular calcium-dependent manner and by mediating influx of extracellular calcium. These data support a model in which OTOP1 acts as a sensor of the extracellular calcium concentration near supporting cells and responds to ATP in the endolymph to increase intracellular calcium levels during otoconia mineralization.
Kim
Euysoo
E
Washington University School of Medicine, Department of Developmental Biology, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Hyrc
Krzysztof L
KL
Speck
Judith
J
Lundberg
Yunxia W
YW
Salles
Felipe T
FT
Kachar
Bechara
B
Goldberg
Mark P
MP
Warchol
Mark E
ME
Ornitz
David M
DM
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002119:Calcium Carbonate / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D003460:Crystallization; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D010037:Otolithic Membrane / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014722:Vestibule, Labyrinth / Q000166:cytology*
D008565:Membrane Proteins; D058470:Receptors, Purinergic P2Y; D011993:Recombinant Fusion Proteins; C479478:otopetrin 1 protein, mouse; D000255:Adenosine Triphosphate; D002119:Calcium Carbonate