Journal Article

Otoferlin interacts with myosin VI: implications for maintenance of the basolateral synaptic structure of the inner hair cell

Paulina Heidrych, Ulrike Zimmermann, Stephanie Kuhn, Christoph Franz, Jutta Engel, Susanne V. Duncker, Bernhard Hirt, Carsten M. Pusch, Peter Ruth, Markus Pfister, Walter Marcotti, Nikolaus Blin and Marlies Knipper

in Human Molecular Genetics

Volume 18, issue 15, pages 2779-2790
Published in print August 2009 | ISSN: 0964-6906
Published online May 2009 | e-ISSN: 1460-2083 | DOI: https://dx.doi.org/10.1093/hmg/ddp213
Otoferlin interacts with myosin VI: implications for maintenance of the basolateral synaptic structure of the inner hair cell

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Otoferlin has been proposed to be the Ca2+ sensor in hair cell exocytosis, compensating for the classical synaptic fusion proteins synaptotagmin-1 and synaptotagmin-2. In the present study, yeast two-hybrid assays reveal myosin VI as a novel otoferlin binding partner. Co-immunoprecipitation assay and co-expression suggest an interaction of both proteins within the basolateral part of inner hair cells (IHCs). Comparison of otoferlin mutants and myosin VI mutant mice indicates non-complementary and complementary roles of myosin VI and otoferlin for synaptic maturation: (i) IHCs from otoferlin mutant mice exhibited a decoupling of CtBP2/RIBEYE and CaV1.3 and severe reduction of exocytosis. (ii) Myosin VI mutant IHCs failed to transport BK channels to the membrane of the apical cell regions, and the exocytotic Ca2+ efficiency did not mature. (iii) Otoferlin and myosin VI mutant IHCs showed a reduced basolateral synaptic surface area and altered active zone topography. Membrane infoldings in otoferlin mutant IHCs indicated disturbed transport of endocytotic membranes and link the above morphological changes to a complementary role of otoferlin and myosin VI in transport of intracellular compartments to the basolateral IHC membrane.

Journal Article.  7687 words.  Illustrated.

Subjects: Genetics and Genomics

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