Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 9, Pages E1028-E1037Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1416424112
Keywords
calcium buffers; exocytosis; calcium current; synapse; hair cell
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Funding
- Humboldt fellowship
- Deutsche Forschungsgemeinschaft (DFG)
- Collaborative Research Center 889 Projects
- German Federal Ministry for Education and Research through the Bernstein Center for Computational Neuroscience [01GQ0811, 01GQ1005A]
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EF-hand Ca2+-binding proteins are thought to shape the spatio-temporal properties of cellular Ca2+ signaling and are prominently expressed in sensory hair cells in the ear. Here, we combined genetic disruption of parvalbumin-a, calbindin-D28k, and calretinin in mice with patch-clamp recording, in vivo physiology, and mathematical modeling to study their role in Ca2+ signaling, exocytosis, and sound encoding at the synapses of inner hair cells (IHCs). IHCs lacking all three proteins showed excessive exocytosis during prolonged depolarizations, despite enhanced Ca2+-dependent inactivation of their Ca2+ current. Exocytosis of readily releasable vesicles remained unchanged, in accordance with the estimated tight spatial coupling of Ca2+ channels and release sites (effective coupling distance of 17 nm). Substitution experiments with synthetic Ca2+ chelators indicated the presence of endogenous Ca2+ buffers equivalent to 1 mM synthetic Ca2+- binding sites, approximately half of them with kinetics as fast as 1,2-Bis(2-aminophenoxy) ethane N, N, N', N'-tetraacetic acid (BAPTA). Synaptic sound encoding was largely unaltered, suggesting that excess exocytosis occurs extrasynaptically. We conclude that EF-hand Ca2+ buffers regulate presynaptic IHC function for metabolically efficient sound coding.
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