CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells
To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the struc...
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eLife Sciences Publications Ltd
2024-12-01
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| Online Access: | https://elifesciences.org/articles/93646 |
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| author | David Oestreicher Shashank Chepurwar Kathrin Kusch Vladan Rankovic Sangyong Jung Nicola Strenzke Tina Pangrsic |
| author_facet | David Oestreicher Shashank Chepurwar Kathrin Kusch Vladan Rankovic Sangyong Jung Nicola Strenzke Tina Pangrsic |
| author_sort | David Oestreicher |
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| description | To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage- and calcium-dependent inactivation of IHC CaV1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding. |
| format | Article |
| id | doaj-art-3f27f7c5bf1143b48a3bc8235f80451e |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-3f27f7c5bf1143b48a3bc8235f80451e2024-12-24T15:38:29ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.93646CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cellsDavid Oestreicher0https://orcid.org/0000-0002-4541-6398Shashank Chepurwar1Kathrin Kusch2Vladan Rankovic3Sangyong Jung4Nicola Strenzke5https://orcid.org/0000-0003-1673-1046Tina Pangrsic6https://orcid.org/0000-0002-7313-1648Experimental Otology Group, InnerEarLab, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany; Auditory Neuroscience Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, GermanyAuditory Systems Physiology Group, Institute for Auditory Neuroscience, InnerEarLab, University Medical Center Göttingen, Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, Göttingen, GermanyFunctional Auditory Genomics, Institute for Auditory Neuroscience, University Medical Center Göttingen, Göttingen, Germany; Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, GermanyInstitute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany; Restorative Cochlear Genomics Group, Auditory Neuroscience and Optogenetics Laboratory, German Primate Cente, Göttingen, GermanyInstitute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, GermanyAuditory Systems Physiology Group, Institute for Auditory Neuroscience, InnerEarLab, University Medical Center Göttingen, Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, Göttingen, GermanyExperimental Otology Group, InnerEarLab, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany; Auditory Neuroscience Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, Göttingen, Germany; Multiscale Bioimaging Cluster of Excellence (MBExC), University of Göttingen, Göttingen, GermanyTo encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage- and calcium-dependent inactivation of IHC CaV1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.https://elifesciences.org/articles/93646DFNB93calcium channelhearing impairmentribbon synapseCACNA1D |
| spellingShingle | David Oestreicher Shashank Chepurwar Kathrin Kusch Vladan Rankovic Sangyong Jung Nicola Strenzke Tina Pangrsic CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells eLife DFNB93 calcium channel hearing impairment ribbon synapse CACNA1D |
| title | CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells |
| title_full | CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells |
| title_fullStr | CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells |
| title_full_unstemmed | CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells |
| title_short | CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells |
| title_sort | cabp1 and 2 enable sustained cav1 3 calcium currents and synaptic transmission in inner hair cells |
| topic | DFNB93 calcium channel hearing impairment ribbon synapse CACNA1D |
| url | https://elifesciences.org/articles/93646 |
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