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Harmonin inhibits presynaptic Cav1.3 Ca2+ channels in mouse inner hair cells

Abstract

Harmonin is a scaffolding protein that is required for normal mechanosensory function in hair cells. We found a presynaptic association of harmonin and Cav1.3 Ca2+ channels at the mouse inner hair cell synapse, which limits channel availability through a ubiquitin-dependent pathway.

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Figure 1: Harmonin inhibits Cav1.3 channels and is localized at IHC synapses.
Figure 2: Dfcr mutation prevents the functional interaction of harmonin and Cav1.3.
Figure 3: Harmonin inhibits plasma membrane Cav1.3 channel density through a ubiquitin-dependent pathway.

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Acknowledgements

The authors thank J. Striessnig for Cacna1d−/− mice, U. Mueller and U. Wolfrum for cDNAs and antibodies, Q. Zheng for Ush1c−/− tissue, H. Couchoux and A. Inagaki for contributing data, B. Fritzsch, C. Harata, M. Stamnes and R. Piper for advice and discussion, and J. Diamond for comments on the manuscript. This work was supported by the US National Institutes of Health (DC009433, HL087120 and DC010362 to A.L., DC008417 to I.E.C.-J., and DA015040 and K12/GM000680 to F.D.G.), the Deafness Research Foundation (A.L. and I.E.C.-J.), the German Research Foundation (Collaborative Research Center 889, project A5, Center for Molecular Physiology of the Brain, FZT-103, T.M.), the German Federal Ministry for Research and Technology (Bernstein Center for Computational Neuroscience Goettingen, 01GQ1005A, T.M.), and an Alexander von Humboldt fellowship to T.P.

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Contributions

F.D.G. conducted the patch-clamp recordings of transfected HEK-293T cells and mouse IHCs. K.E.B. performed the biochemical and immunofluorescence analyses of ubiquitinated channels. T.P. performed the Ca2+ imaging of mouse IHCs. I.E.C.-J. performed the biochemical characterizations of harmonin/Cav1.3 interactions. T.M. and A.L. assisted with experimental design, data analysis and interpretation. All of the authors contributed to writing of the manuscript.

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Correspondence to Amy Lee.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 418 kb)

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Gregory, F., Bryan, K., Pangršič, T. et al. Harmonin inhibits presynaptic Cav1.3 Ca2+ channels in mouse inner hair cells. Nat Neurosci 14, 1109–1111 (2011). https://doi.org/10.1038/nn.2895

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