When the hair bundle of a mammalian cochlear hair cell is deflected, the mechanoelectrical transduction (MET) current first activates and then decays (adapts) in two kinetically distinct phases: a fast, sub-millisecond-to-few-millisecond component and a slower, Ca2+-dependent component. Experiments have established that Ca2+ entry through MET channels does not drive fast adaptation, and that the classical myosin-1c motor model of slow adaptation is not supported in mammals, leaving the mechanism of both components unidentified. The problem is to determine the physical and molecular basis of fast adaptation (passive viscoelastic relaxation of the hair bundle and gating springs, intrinsic channel gating kinetics, or another process) and of slow adaptation, and to show how the identified mechanism quantitatively produces the observed dual-timescale current decay, the slow mechanical drift (creep) of the deflected bundle, and stimulus-modality-dependent manifestations. The question originates from Caprara, Mecca, Wang, Ricci and Peng (2019), who ruled out Ca2+ entry as the fast-adaptation driver and called for new molecular models; follow-up work has refuted the motor model for slow adaptation, measured viscoelastic bundle mechanics, built quantitative viscoelastic models of fast adaptation, and proposed a pathway in which the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) acting through the MET-complex protein TMIE drives slow adaptation, but no mechanism has been experimentally established.

Background

Auditory hair cells of the mammalian cochlea convert sound-induced vibration into electrical signals. Their apical hair bundle, a staircase array of actin-filled stereocilia, carries mechano-electrical transduction (MET) ion channels near the tips of the shorter stereocilia. The channels are opened by tension in tip links, extracellular filaments (made of cadherin-23 and protocadherin-15) that connect the tip of each shorter stereocilium to the side of its taller neighbor; the elastic element transmitting force to the channel is conventionally called the gating spring. During a sustained deflection the MET current decays, a property called adaptation, which is thought to set the hair cell's dynamic range and to shape frequency tuning. Two components are distinguished kinetically: fast adaptation (sub-millisecond to a few milliseconds) and slow adaptation (tens of milliseconds). For decades both were explained by calcium: Ca2+ entering through the open MET channel was proposed to reclose the channel (fast adaptation), and a myosin-1c molecular-motor complex climbing actin at the upper tip-link insertion was proposed to readjust tip-link tension (slow adaptation). Work on rat cochlear hair cells overturned this picture for mammals: altering Ca2+ entry or intracellular Ca2+ buffering barely affects adaptation kinetics, and fast adaptation persists at depolarized potentials where Ca2+ entry is negligible (Peng, Effertz and Ricci, Neuron 2013; Caprara et al., Journal of Neuroscience 2019, the source of this problem). Caprara et al. further showed, using high-speed imaging, that fluid-jet (force-step) stimuli produce a complex creep — a slow ongoing mechanical drift — of the bundle displacement that masks the fast component, which reconciled earlier conflicting fluid-jet data that had suggested Ca2+-dependent fast adaptation; a slower Ca2+-dependent process remains. The motor model of slow adaptation is also difficult to reconcile with mammalian data: MET channels sit at the lower tip-link insertions on the short stereocilia, far from the upper insertion site where the motor complex was proposed to act, and adaptation shifts occur at positive membrane potentials without accompanying slow current decays. Caprara, Mecca and Peng (Science Advances 2020) subsequently showed that the motor model's key evidence, a correlation between slow adaptation and hair-bundle creep, fails in mice, rats and gerbils. The MET channel complex is itself only partially characterized: transmembrane channel-like proteins TMC1/TMC2 with auxiliary subunits (TMIE, LHFPL5, CIB2) form the candidate channel, and its gating mechanism remains under active investigation (Qiu and Müller, Neuron 2022; Caprara and Peng 2022). Direct measurements have now demonstrated two viscoelastic-like mechanical processes in the mammalian hair bundle (Peng et al. 2021), and experimentally constrained models argue that viscoelastic adaptation elements can quantitatively account for fast adaptation (Chatterjee and Ó Maoiléidigh 2026), but the molecular and structural elements implementing either adaptation process have not been identified, and the mechanism of slow adaptation has only an unrefereed molecular proposal (an interaction between the membrane lipid PIP2 and the MET-complex protein TMIE).

Problem Statement

What is the physical and molecular basis of mechanotransduction adaptation in mammalian cochlear hair cells? Specifically: (i) identify the mechanism of fast adaptation, the sub-millisecond-to-few-millisecond decay of the mechanoelectrical transduction (MET) current that is established to be independent of Ca2+ entry through the MET channels, and determine which structure implements it, for example passive viscoelastic relaxation (spring-and-dashpot behavior) of the gating springs and hair bundle, intrinsic gating kinetics of the channel, or another process; and (ii) identify the mechanism of slow adaptation in mammalian cochlear hair cells, replacing the classical myosin-1c motor model that current evidence does not support. A complete answer identifies the responsible molecular or structural elements, justifying the mechanism against the competing alternatives rather than merely restating a mechanism that the literature has already proposed, and shows quantitatively how they produce the observed phenomenology: the dual-timescale decay of the MET current, the Ca2+-independence of the fast component and Ca2+-dependence of the slow component, the mechanical creep of the hair bundle under force-step stimulation, and the different manifestations of adaptation under stiff-probe (displacement-step) versus fluid-jet (force-step) stimulation.

References

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