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1.A.110.  The Channel-forming Otopetrin (OTOP) Family 

Otopertrin1 of Danio rerio inhibits P2Y purinoceptors. It has been reprted to modulate calcium homeostasis and influx of calcium in response to extracellular ATP. It is essential for the formation of otoliths in the inner ear of developing larvae and for the perception of gravity and acceleration (Söllner et al. 2004; ).  Otoliths in bony fishes and otoconia in mammals are composite crystals consisting of calcium carbonate and proteins. These biominerals are part of the gravity and linear acceleration detection system of the inner ear. Mutations in otopetrin 1 result in lack of otoconia in tilted and mergulhador mutant mice. Söllner et al. 2004 showed that a mutation in the orthologous gene in zebrafish is responsible for the complete absence of otoliths. They examined the localization of Starmaker, a secreted protein that is abundant in otoliths in backstroke mutants. The starmaker protein accumulated within cells of the otic epithelium, indicating a possible defect in secretion.

The fish inner ear contains three large extracellular biomineral particles, otoliths, which have evolved to transduce the force of gravity into neuronal signals. Mammalian ears contain thousands of small particles called otoconia that serve a similar function. Loss or displacement of these structures can be lethal for fish and is responsible for benign paroxysmal positional vertigo (BPPV) in humans. The distinct morphologies of otoconial particles and otoliths suggest divergent developmental mechanisms. Mutations in Otopetrin 1 result in nonsyndromic otoconial agenesis and a severe balance disorder in mice. Hughes et al. 2004 showed that in zebrafish,  Otop1 is essential for otolith formation. Morpholino-mediated knockdown of zebrafish Otop1 led to otolith agenesis without affecting the sensory epithelium or other structures within the inner ear. Otop1 regulates cellular Ca2+ (Hughes et al. 2007). The OTOP family was previously the DUF270 or pfam03189 family. The members of this family have three "Otopetrin Domains" that are highly conserved between vertebrates, arthropods and nematodes, as well as a constrained predicted loop structure (Hughes et al. 2008). 

By comparative transcriptome analysis of mouse taste receptor cells, Tu et al. 2018 identified OTOP1 as a proton-selective ion channel. They found that murine OTOP1 is enriched in acid-detecting taste receptor cells and is required for their zinc-sensitive proton conductance. Two related murine genes, Otop2 and Otop3, and a Drosophila ortholog also encode proton channels. Evolutionary conservation of the gene family and its widespread tissue distribution suggest a broad role for proton channels in physiology and pathophysiology (Tu et al. 2018).

References associated with 1.A.110 family:

Hughes, I., B. Blasiole, D. Huss, M.E. Warchol, N.P. Rath, B. Hurle, E. Ignatova, J.D. Dickman, R. Thalmann, R. Levenson, and D.M. Ornitz. (2004). Otopetrin 1 is required for otolith formation in the zebrafish Danio rerio. Dev Biol 276: 391-402. 15581873
Hughes, I., J. Binkley, B. Hurle, E.D. Green, , A. Sidow, and D.M. Ornitz. (2008). Identification of the Otopetrin Domain, a conserved domain in vertebrate otopetrins and invertebrate otopetrin-like family members. BMC Evol Biol 8: 41. 18254951
Hughes, I., M. Saito, P.H. Schlesinger, and D.M. Ornitz. (2007). Otopetrin 1 activation by purinergic nucleotides regulates intracellular calcium. Proc. Natl. Acad. Sci. USA 104: 12023-12028. 17606897
Söllner, C., H. Schwarz, R. Geisler, and T. Nicolson. (2004). Mutated otopetrin 1 affects the genesis of otoliths and the localization of Starmaker in zebrafish. Dev Genes Evol 214: 582-590. 15480759
Tu, Y.H., A.J. Cooper, B. Teng, R.B. Chang, D.J. Artiga, H.N. Turner, E.M. Mulhall, W. Ye, A.D. Smith, and E.R. Liman. (2018). An evolutionarily conserved gene family encodes proton-selective ion channels. Science 359: 1047-1050. 29371428