Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells

Euysoo Kim, Krzysztof L. Hyrc, Judith Speck, Felipe T. Salles, Yunxia W Lundberg, Mark P. Goldberg, Bechara Kachar, Mark E. Warchol, David M. Ornitz

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Otopetrin 1 (Otop1) encodes a protein that is essential for the development of otoconia. Otoconia are the extracellular calcium carbonate containing crystals that are important for vestibular mechanosensory transduction of linear motion and gravity. There are two mutant alleles of Otop1 in mice, titled (tlt) and mergulhador (mlh), which result in non-syndromic otoconia agenesis and a consequent balance defect. Biochemically, Otop1 has been shown to modulate purinergic control of intracellular calcium in vestibular supporting cells, which could be one of the mechanisms by which Otop1 participates in the mineralization of otoconia. To understand how tlt and mlh mutations affect the biochemical function of Otop1, we examined the purinergic response of COS7 cells expressing mutant Otop1 proteins, and dissociated sensory epithelial cells from tlt and mlh mice. We also examined the subcellular localization of Otop1 in whole sensory epithelia from tlt and mlh mice. Here we show that tlt and mlh mutations uncouple Otop1 from inhibition of P2Y receptor function. Although the in vitro biochemical function of the Otop1 mutant proteins is normal, in vivo they behave as null alleles. We show that in supporting cells the apical membrane localization of the mutant Otop1 proteins is lost. These data suggest that the tlt and mlh mutations primarily affect the localization of Otop1, which interferes with its ability to interact with other proteins that are important for its cellular and biochemical function.

Original languageEnglish (US)
Pages (from-to)655-661
Number of pages7
JournalMolecular and Cellular Neuroscience
Volume46
Issue number3
DOIs
StatePublished - Mar 1 2011

Fingerprint

Otolithic Membrane
Missense Mutation
Mutation
Cellular Mechanotransduction
Proteins
Alleles
Calcium Carbonate
Gravitation
Mutant Proteins
Epithelium
Epithelial Cells
Cell Membrane
Calcium

Keywords

  • Calcium
  • Otoconia
  • Otopetrin
  • Purinergic signaling
  • Vestibular

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells. / Kim, Euysoo; Hyrc, Krzysztof L.; Speck, Judith; Salles, Felipe T.; Lundberg, Yunxia W; Goldberg, Mark P.; Kachar, Bechara; Warchol, Mark E.; Ornitz, David M.

In: Molecular and Cellular Neuroscience, Vol. 46, No. 3, 01.03.2011, p. 655-661.

Research output: Contribution to journalArticle

Kim, Euysoo ; Hyrc, Krzysztof L. ; Speck, Judith ; Salles, Felipe T. ; Lundberg, Yunxia W ; Goldberg, Mark P. ; Kachar, Bechara ; Warchol, Mark E. ; Ornitz, David M. / Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells. In: Molecular and Cellular Neuroscience. 2011 ; Vol. 46, No. 3. pp. 655-661.
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