TRPV-Dependent Gain Control of Mechanical Amplification in an Ear

Description

Abstract (English)

By amplifying sound-induced vibrations in an intensity- and frequency specific manner, ears can sharpen their resonant
mechanics. Ears boost their mechanical input with motile auditory receptors. In Drosophila, this mechanical amplification is
controlled by heteromeric TRPV channels formed by Nanchung (Nan) and Inactive (Iav) (Nan-Iav).
Nan-Iav promote calcium entry into auditory receptors and can be activated in vitro by nicotinamide (NAM), an intermediate
metabolite of the NAD-salvage pathway. We identify NAM as a direct, endogenous ligand of these TRPV channels, regulating
their activity in vivo, in auditory receptors, and, thus, the mechanical amplification gain in the ear. NAM is enzymatically removed
by nicotinamidase (Naam), allowing for a regulation of TRPV activity. Both, nicotinamidase and TRPV activity are matched to
each other, with calcium modulating the activity of nicotinamidase by binding to its EF-hand motifs.
Thus, we can establish in vivo ligand-gating of TRPV channels by a cell-autonomous mechanism that allows to couple auditory
mechanics to the metabolic state of the auditory receptors. Here, NAM-activated TRPV channels result in calcium-influx that
subsequently enhances NAM turnover, providing a molecular feedback loop that allows to adjust the mechanical feedback gain by
regulating auditory receptor motility.