| First Author | Jung S | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 24 | Pages | E3141-9 |
| PubMed ID | 26034270 | Mgi Jnum | J:223388 |
| Mgi Id | MGI:5648761 | Doi | 10.1073/pnas.1417207112 |
| Citation | Jung S, et al. (2015) Rab3-interacting molecules 2alpha and 2beta promote the abundance of voltage-gated CaV1.3 Ca2+ channels at hair cell active zones. Proc Natl Acad Sci U S A 112(24):E3141-9 |
| abstractText | Ca(2+) 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 2alpha and beta (RIM2alpha and RIM2beta) in clustering voltage-gated CaV1.3 Ca(2+) channels at the AZs of sensory inner hair cells (IHCs). We show that IHCs of hearing mice express mainly RIM2alpha, but also RIM2beta and RIM3gamma, which all localize to the AZs, as shown by immunofluorescence microscopy. Immunohistochemistry, patch-clamp, fluctuation analysis, and confocal Ca(2+) imaging demonstrate that AZs of RIM2alpha-deficient IHCs cluster fewer synaptic CaV1.3 Ca(2+) channels, resulting in reduced synaptic Ca(2+) influx. Using superresolution microscopy, we found that Ca(2+) 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 Ca(2+) current, whereas the apparent Ca(2+) dependence of exocytosis was unchanged. Hair cell-specific deletion of all RIM2 isoforms caused a stronger reduction of Ca(2+) 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 RIM2alpha. We conclude that RIM2alpha and RIM2beta promote a large complement of synaptic Ca(2+) channels at IHC AZs and are required for normal hearing. |
