Mammals react to sounds with exquisite tem-poral fidelity, a feat that is initiated by precise calcium-dependent signalling in the hair cells of the inner ear. Calcium is a common signal-ling molecule in the nervous system and else-where. Writing in Cell, Roux et al.1 describe how they have identified an unexpected player in the auditory system. That player is a mol-ecule called otoferlin, which has not previously been implicated as a calcium sensor for neuro-transmitter release in nerve function.A sensitive auditory system confers a tremen-dous evolutionary advantage, as it protects us from the things we fear most — those we can-not see. The ability to localize these potential dangers or communicate these possible threats depends on the precise timing of signals in the neural code that the brain ultimately perceives as sound. The basis of this temporal fidelity lies in the control of communication between the mechanosensory cell of the cochlea, the inner hair cell, and its downstream partner, the audi-tory nerve (Fig. 1). The mechanical energy of acoustic waves causes minute displacements of sensory hair bundles extending from the cell. These deflections result in rapidly oscil-lating electrical potentials, which trigger cal-cium influx from outside the cell; that in turn prompts tiny subcellular organelles filled with a chemical messenger to dump their contents into a well-defined extracellular compartment, the synaptic cleft. This messenger, or neuro-transmitter, excites a nearby, afferent nerve fibre, which elicits an all-or-none electrical response that propagates details of the acoustic stimulus to the brain. The capacity of the auditory system to follow acoustic waves oscillating at several thousand times per second suggests that this calcium-dependent regulatory event may need to be as much as ten times more precise than signalling between most types of neuron. So how does the inner hair cell achieve such exquisite tem-poral fidelity in its release of neurotransmit-ter? Roux et al.1 suggest that the hair cell has evolved a unique calcium-sensing molecule, otoferlin, for controlling neurotransmitter release. The action of otoferlin allows a hair cell’s specialized synapses — ribbon synapses, a specific class of afferent synapse common to sensory systems — to meet the requirements of hearing. Both mice and humans suffer from an inher-ited form of deafness called DFNB9. Defects in otoferlin are responsible, and Roux and col-leagues hypothesized that otoferlin might be involved in the correct operation of the synapse between the hair cell and the afferent nerve fibre. They found that, in mice, not only is otof-erlin localized to the synaptic vesicles of inner hair cells, but that it also undergoes develop-mental changes in expression concurrent with the formation of ribbon synapses. Otoferlin also binds in a calcium-dependent manner to SNARE proteins, highly conserved molecules thought to be essential for the release of neuro-transmitters and for other events requiring fusion of membranes. The authors genetically manipulated the otoferlin molecule to prevent its functional expression. Mice lacking both copies of the normal gene have structurally normal synapses between the hair cell and afferent fibre, but are deaf and lack calcium-triggered dumping of the synaptic-vesicle contents. Interestingly, only the most rapid phase of putative neuro-transmitter release is abolished by a defect in the otoferlin molecule. This fast component is widely thought to be associated with a special-ized class of the vesicles that are close to the cell surface and molecularly poised for release (Fig. 1).This paper1 is of great interest to both spe-cialists in hearing research and neuroscien-tists in general, for several reasons. First, the mystery of the molecular entity mediating the temporal fidelity of signalling by the primary synapse in the auditory system may now be solved. At most fast synapses, the transmem-brane protein synaptotagmin I is thought to be the calcium sensor of fast, synchronized neurotransmitter release2,3. Thus, the possibil-ity that the hair-cell synapse, or perhaps even other synapses, use a different molecule for calcium sensing is intriguing. Second, all synaptotagmin molecules have so-called C2 domains, putative calcium-bind-ing regions that are proposed to be responsible for its calcium-sensing functions4,5. Otoferlin contains six of these C2 domains, presumably for the binding of calcium, but it remains to be seen if or how other parts of the otoferlin molecule contribute to the unique properties of calcium-dependent signalling by the coch-lear inner hair cell. Third, the new work raises the question of whether otoferlin or related molecules have a function at conventional synapses. Ferlin family members in non-neuronal cells have been identified as partici-pants in membrane fusion events related to membrane repair6. Finally, Roux and colleagues’ experiments1 show how difficult it is to ascribe specific func-tions to molecules essential to synaptic-vesicle cycling. It is puzzling that the inner hair cell Hair bundleabActive zoneSynaptic vesiclesRibbonReadily releasable poolof vesiclesCalcium channelsSynaptic cleftPost-synapticreceptorsCochlearhair cellAfferent nerve fibreAfferent nerve fibreAuditory nerveFigure 1 | Sound reception and perception. a, In the mammalian ear, the hair bundle on a cochlear hair cell senses variations in sound-induced pressure in the cochlea. The resulting, voltage-dependent signal is transduced and passed via the afferent nerve fibre and the auditory nerve to the brain, where it is perceived as sound. b, The voltage-dependent signal in the hair cell controls calcium channels, prompting calcium influx from outside the cell. Consequent changes in the cell’s active zone result in neurotransmitter release into the synaptic cleft. In the active zone, aggregates of neurotransmitter-containing vesicles are tethered to a structure called the synaptic ribbon, localized to concentrated sites of calcium influx. A subpopulation of these vesicles lies close to the hair-cell membrane and constitutes a readily released source of neurotransmitter. Roux et al.1 show that otoferlin is essential for the function of the auditory ribbon synapse, probably through its calcium-binding ability. NEUROBIOLOGYAuditory fidelityThomas D. ParsonsDetailed investigation of a molecule involved in an inherited type of deafness reveals a fresh facet to the