, 2010). OHC forces generated from changes in length of the cell-body are attributed to perturbations in cell membrane potential triggered by current entering through the mechanotransduction (MT) channels in the stereocilia.

These somatic forces have been traced to the protein prestin that is densely packed into the cell’s basolateral membrane, and which undergoes rapid changes of area when the receptor potential changes. Isolated OHCs generate forces in response to voltage stimuli Cilengitide ic50 up to at least 80 kHz (Frank et al., 1999). In the intact cochlea, however, the electrical filtering effect of the cell membrane, effectively possessing an electrical time constant = RmCm, would reduce potential changes to negligible levels at

any significant acoustic frequencies. Consequently, even though prestin-knockout mice are deaf (Liberman et al., 2002 and Mellado-Lagarde et al., 2008), the proposal that the prestin-dependent cell body forces account for functional amplification in the Venetoclax chemical structure cochlea has never quite held together. The central issue is known as the “RC time-constant problem.” There have been numerous solutions proposed to address this conundrum. However, the paper by Johnson et al. (2011) in this issue of Neuron indicates a clear way out of the impasse for prestin-based mechanisms, for it shows that the OHC time constants may have been significantly overestimated. Methods for recording in the mammalian cochlea have developed slowly compared to recordings Casein kinase 1 made in other vertebrate species, and it is only relatively recently that reliable recordings of transduction currents have been made

from mature mammalian hair cells. Johnson et al. (2011) have recorded from both rats and gerbils where OHCs can be selected from known frequency points along the cochlea. By measuring the transduction and basolateral membrane currents in OHCs from different cochlear positions in excised cochleas, the paper shows that the OHC membrane filtering may be an order of magnitude less than previously thought. As a result, receptor potentials would be uniformly larger. The authors present several lines of experimental evidence to support these arguments. First, they find that MT channel currents are significantly larger when recorded from OHCs taken toward the high-frequency end of the cochlea. This observation has been inferred several times from in silico cochlear model studies (Mammano and Nobili, 1993 and Ramamoorthy et al., 2007) and is seen in data from nonmammalian cochleas, but the records here show the effect clearly in mammalian hair cells. Second, the paper shows that resting transducer currents, irrespective of cochlear place of origin, are further enhanced when the OHC stereocilia face low Ca2+ concentrations (20 μM) as they do in the living cochlea (in vivo the stereocilia project into a low Ca2+/high K+ containing compartment, referred to as the scala media).