Synaptic contributions to cochlear outer hair cell Ca²⁺homeostasis

Abstract

For normal cochlear function, outer hair cells (OHCs) require a precise regulation of intracellular Ca2+ levels. Influx of Ca2+ occurs both at the stereocillia tips and through the basolateral membrane. In this latter compartment, two different origins for Ca2+ influx have been poorly explored: voltage-gated Ca2+ channels (VGCC) at synapses with type II afferent neurons, and α9α10 cholinergic nicotinic receptors at synapses with medio-olivochlear complex (MOC) neurons. Using functional imaging, we report that these two Ca2+ entry sites are closely positioned, but present different regulation mechanisms. Ca2+ spread from MOC synapses is contained by cisternal Ca2+-ATPases. Considered a weak drive for transmitter release, we found that VGCC Ca2+ signals are larger than expected and can be potentiated by ryanodine receptors. Finally, we showed that sorcin, a highly expressed gene product in OHCs with reported Ca2+ control function in cardiomyocytes, regulates basal Ca2+ levels and MOC synaptic activity in OHCs.

Loss of Choline Agonism in the Inner Ear Hair Cell Nicotinic Acetylcholine Receptor Linked to the α10 Subunit

“…Finally, compared to chicken, the mammalian α9α10 receptor shows greater desensitization to ACh and higher calcium permeability (Lipovsek et al, 2012(Lipovsek et al, , 2014Marcovich et al, 2020). In addition, the postsynaptic space delimited by a closely juxtaposed subsynaptic cistern is more restricted in mammals (Fuchs et al, 2014;Im et al, 2014), which may contribute to elicit highly localized α9α10-dependent rises in calcium concentration uncoupled from internal calcium stores (Moglie et al, 2018(Moglie et al, , 2020. Together with the poorer choline agonism, these multiple functional adaptations may have contributed to ''tighter'' ACh responses, which may prove fundamental to faithfully reproduce the high frequency activity of efferent medial olivocochlear fibers (Ballestero et al, 2011), therefore fine-tuning the modulation of the OHC cochlear amplifier and contributing to the expansion of the mammalian hearing range.…”