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  Rab3-interacting molecules 2 alpha and 2 beta promote the abundance of voltage-gated Ca(V)1.3 Ca2+ channels at hair cell active zones.

Jung, S. Y., Oshima-Takago, T., Chakrabarti, R., Wong, A. B., Jing, Z. Z., Yamanbaeva, G., et al. (2015). Rab3-interacting molecules 2 alpha and 2 beta promote the abundance of voltage-gated Ca(V)1.3 Ca2+ channels at hair cell active zones. Proceedings of the National Academy of Sciences of the United States of America, 112(24), E3141-E3149. doi:10.1073/pnas.1417207112.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-BB37-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-D6D7-6
Genre: Journal Article

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 Creators:
Jung, S. Y., Author
Oshima-Takago, T., Author
Chakrabarti, R., Author
Wong, A. B., Author
Jing, Z. Z., Author
Yamanbaeva, G., Author
Picher, M. M., Author
Wojcik, S. M., Author
Göttfert, F.1, Author              
Predoehl, F., Author
Michel, K., Author
Hell, S. W.1, Author              
Schoch, S., Author
Strenzke, N., Author
Wichmann, C., Author
Moser, T., Author
Affiliations:
1Department of NanoBiophotonics, MPI for Biophysical Chemistry, Max Planck Society, ou_578627              

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Free keywords: Rab3-interacting molecule; active zone; ribbon synapse; Ca2+ channel; vesicle
 Abstract: Ca2+ influx triggers the fusion of synaptic vesicles at the presynaptic active zone (AZ). Here we demonstrate a role of Ras-related in brain 3 (Rab3)-interacting molecules 2 alpha and beta (RIM2 alpha and RIM2 beta) in clustering voltage-gated Ca(V)1.3 Ca2+ channels at the AZs of sensory inner hair cells (IHCs). We show that IHCs of hearing mice express mainly RIM2 alpha, but also RIM2 beta and RIM3., which all localize to the AZs, as shown by immunofluorescence microscopy. Immunohistochemistry, patch-clamp, fluctuation analysis, and confocal Ca2+ imaging demonstrate that AZs of RIM2 alpha-deficient IHCs cluster fewer synaptic Ca(V)1.3 Ca2+ channels, resulting in reduced synaptic Ca2+ influx. Using superresolution microscopy, we found that Ca2+ channels remained clustered in stripes underneath anchored ribbons. Electron tomography of high-pressure frozen synapses revealed a reduced fraction of membrane-tethered vesicles, whereas the total number of membrane-proximal vesicles was unaltered. Membrane capacitance measurements revealed a reduction of exocytosis largely in proportion with the Ca2+ current, whereas the apparent Ca2+ dependence of exocytosis was unchanged. Hair cell-specific deletion of all RIM2 isoforms caused a stronger reduction of Ca2+ influx and exocytosis and significantly impaired the encoding of sound onset in the postsynaptic spiral ganglion neurons. Auditory brainstem responses indicated a mild hearing impairment on hair cell-specific deletion of all RIM2 isoforms or global inactivation of RIM2 alpha. We conclude that RIM2 alpha and RIM2 beta promote a large complement of synaptic Ca2+ channels at IHC AZs and are required for normal hearing.

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Language(s): eng - English
 Dates: 2015-06-16
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1417207112
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Title: Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 112 (24) Sequence Number: - Start / End Page: E3141 - E3149 Identifier: -