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Disruption of adaptor protein 2μ ( AP ‐2μ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing
Author(s) -
Jung SangYong,
Maritzen Tanja,
Wichmann Carolin,
Jing Zhizi,
Neef Andreas,
Revelo Natalia H,
AlMoyed Hanan,
Meese Sandra,
Wojcik Sonja M,
Panou Iliana,
Bulut Haydar,
Schu Peter,
Ficner Ralf,
Reisinger Ellen,
Rizzoli Silvio O,
Neef Jakob,
Strenzke Nicola,
Haucke Volker,
Moser Tobias
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201591885
Subject(s) - biology , signal transducing adaptor protein , microbiology and biotechnology , synaptic vesicle , neuroscience , vesicle , signal transduction , biochemistry , membrane
Active zones ( AZ s) of inner hair cells ( IHC s) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2μ ( AP ‐2μ) is required for release site replenishment and hearing. We show that hair cell‐specific disruption of AP ‐2μ slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane‐proximal vesicles and intact endocytic membrane retrieval. Sound‐driven postsynaptic spiking was reduced in a use‐dependent manner, and the altered interspike interval statistics suggested a slowed reloading of release sites. Sustained strong stimulation led to accumulation of endosome‐like vacuoles, fewer clathrin‐coated endocytic intermediates, and vesicle depletion of the membrane‐distal synaptic ribbon in AP ‐2μ‐deficient IHC s, indicating a further role of AP ‐2μ in clathrin‐dependent vesicle reformation on a timescale of many seconds. Finally, we show that AP ‐2 sorts its IHC ‐cargo otoferlin. We propose that binding of AP ‐2 to otoferlin facilitates replenishment of release sites, for example, via speeding AZ clearance of exocytosed material, in addition to a role of AP ‐2 in synaptic vesicle reformation.