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The Journal of Neuroscience, October 18, 2006, 26(42):10777-10788; doi:10.1523/JNEUROSCI.1847-06.2006

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Cellular/Molecular
Stereociliary Myosin-1c Receptors Are Sensitive to Calcium Chelation and Absent from Cadherin 23 Mutant Mice

Kelli R. Phillips,^1,2 Song Tong,^1,3 Richard Goodyear,⁴ Guy P. Richardson,⁴ and Janet L. Cyr^1,2,3

¹Sensory Neuroscience Research Center and Departments of ²Biochemistry and Molecular Pharmacology and ³Otolaryngology, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9303, and ⁴School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, United Kingdom

Correspondence should be addressed to Dr. Janet L. Cyr, West Virginia University School of Medicine, Sensory Neuroscience Research Center, P.O. Box 9303, One Medical Center Drive, Morgantown, WV 26506-9303. Email: jcyr{at}hsc.wvu.edu

The identities of some of the constituents of the hair-cell transduction apparatus have been elucidated only recently. The molecular motor myosin-1c (Myo1c) functions in adaptation of the hair-cell response to sustained mechanical stimuli and is therefore an integral part of the transduction complex. Recent data indicate that Myo1c interacts in vitro with two other molecules proposed to be important for transduction: cadherin 23 (Cdh23), a candidate for the stereociliary tip link, and phosphatidylinositol 4,5-bisphosphate (PIP₂), which is abundant in the membranes of hair-cell stereocilia. It is not known, however, whether these interactions occur in hair cells. Using an in situ binding assay on saccular hair cells, we demonstrated previously that Myo1c interacts with molecules at stereociliary tips, the site of transduction, through sequences contained within its calmodulin (CaM)-binding neck domain, which can bind up to four CaM molecules. In the current study, we identify the second CaM-binding IQ domain as a region of Myo1c that mediates CaM-sensitive binding to stereociliary tips and to PIP₂ immobilized on a solid support. Binding of Myo1c to stereociliary tips of cochlear and vestibular hair cells is disrupted by treatments that break tip links. In addition, Myo1c does not bind to stereocilia from mice whose hair cells lack Cdh23 protein despite the presence of PIP₂ in the stereociliary membranes. Collectively, our data suggest that Myo1c and Cdh23 interact at the tips of hair-cell stereocilia and that this interaction is modulated by CaM.

Key words: myosin 1c; hair cell; calmodulin; cadherin 23; phosphatidylinositol 4,5-bisphosphate; IQ domain

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Received May 1, 2006; revised Sept. 8, 2006; accepted Sept. 8, 2006.

Correspondence should be addressed to Dr. Janet L. Cyr, West Virginia University School of Medicine, Sensory Neuroscience Research Center, P.O. Box 9303, One Medical Center Drive, Morgantown, WV 26506-9303. Email: jcyr{at}hsc.wvu.edu

This article has been cited by other articles:

				Z. Xu, A. W. Peng, K. Oshima, and S. Heller MAGI-1, A Candidate Stereociliary Scaffolding Protein, Associates with the Tip-Link Component Cadherin 23 J. Neurosci., October 29, 2008; 28(44): 11269 - 11276. [Abstract] [Full Text] [PDF]

				R. J. Goodyear, J. E. Gale, K. M. Ranatunga, C. J. Kros, and G. P. Richardson Aminoglycoside-Induced Phosphatidylserine Externalization in Sensory Hair Cells Is Regionally Restricted, Rapid, and Reversible J. Neurosci., October 1, 2008; 28(40): 9939 - 9952. [Abstract] [Full Text] [PDF]

				A. Li, J. Xue, and E. H. Peterson Architecture of the Mouse Utricle: Macular Organization and Hair Bundle Heights J Neurophysiol, February 1, 2008; 99(2): 718 - 733. [Abstract] [Full Text] [PDF]

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