Unconventional molecular regulation of synaptic vesicle replenishment in cochlear inner hair cells

作者：Vogl Christian^*; Cooper Benjamin H; Neef Jakob; Wojcik Sonja M; Reim Kerstin; Reisinger Ellen; Brose Nils; Rhee Jeong Seop; Moser Tobias; Wichmann Carolin

来源：Journal of Cell Science, 2015, 128(4): 638-644.

DOI：10.1242/jcs.162099

• Ribbon synapse
• Priming
• Tether
• Munc13
• CAPS
• Otoferlin

Ribbon synapses of cochlear inner hair cells (IHCs) employ efficient vesicle replenishment to indefatigably encode sound. In neurons, neuroendocrine and immune cells, vesicle replenishment depends on proteins of the mammalian uncoordinated 13 (Munc13, also known as Unc13) and Ca2+-dependent activator proteins for secretion (CAPS) families, which prime vesicles for exocytosis. Here, we tested whether Munc13 and CAPS proteins also regulate exocytosis in mouse IHCs by combining immunohistochemistry with auditory systems physiology and IHC patch-clamp recordings of exocytosis in mice lacking Munc13 and CAPS isoforms. Surprisingly, we did not detect Munc13 or CAPS proteins at IHC presynaptic active zones and found normal IHC exocytosis as well as auditory brainstem responses (ABRs) in Munc13 and CAPS deletion mutants. Instead, we show that otoferlin, a C-2-domain protein that is crucial for vesicular fusion and replenishment in IHCs, clusters at the plasma membrane of the presynaptic active zone. Electron tomography of otoferlin-deficient IHC synapses revealed a reduction of short tethers holding vesicles at the active zone, which might be a structural correlate of impaired vesicle priming in otoferlin-deficient IHCs. We conclude that IHCs use an unconventional priming machinery that involves otoferlin.

• 出版日期2015-2-15