Cochlear function in mice with only one copy of the <i>prestin</i> gene

Cheatham, Mary Ann; Zheng, Jing; Huynh, K. H.; Du, Guo Guang; Gao, Jiangang; Zuo, Jian; Navarrete, Enrique; Dallos, Peter

doi:10.1113/jphysiol.2005.093518

Cited by 46 publications

(61 citation statements)

References 48 publications

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“…Cheatham and colleagues demonstrated that measurements of nonlinear capacitance in isolated OHCs, as well as the voltage dependence and sensitivity of motor function, did not differ in the heterozygote knockout and wild-type mice, and neither did auditory threshold and frequency selectivity. These results suggest that one copy of the pres gene is able to compensate for the deleted copy and that heterozygous mice do not suffer hearing impairment (20).…”

Section: Introductionmentioning

confidence: 69%

A new mutation in the human pres gene and its effect on prestin function

Tóth¹,

Deák²,

Fazakas³

et al. 2007

Int J Mol Med

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Abstract. The electromotility of cochlear outer hair cells (OHCs) is a major factor in cochlear amplification that enhances the sensitivity of hearing in humans. Prestin is associated with presumed conformational changes in an integral membrane protein. Prestin knockout (-/-) mice display loss of OHC electromotility and a 40-to 60-dB reduction in cochlear sensitivity in vivo. In the present study we described the results of a direct sequencing mutation in the pres gene that was found in genetic screening performed in 47 patients characterized by non-syndromic, mild-to-moderate hearing impairment (30-70 dB) and in 50 control subjects from Hungary, after exclusion of GJB (GJB2, GJB6) mutations in the background. Only one patient and his normal-hearing father showed a heterozygous missense mutation (R150Q/ WT) in the 6th coding exon of the pres gene. None of the 50 control subjects with normal hearing carried this mutation. Electrophysiological studies on the R150Q (homozygous and heterozygous) prestin mutant transiently transfected into reporting cells demonstrated nonlinear capacitance functions (NLC) as a signature of OHC electromotility. The capacitance function in human kidney cell line TSA 201 was similar for wild-type prestin and the mutant. However, for the mutant the voltage where the maximal charge displacement occurred (V 1/2 ) significantly shifted in the hyperpolarizing direction (~15 mV). This is the first genetic and electrophysiological analysis of a human mutation in a coding exon of the pres gene by 47 patients with non-syndromic, sensorineural, mildto-moderate hearing impairment; although the pathogenic role of the R150Q mutation is not unambiguous.

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Section: Introductionmentioning

confidence: 69%

A new mutation in the human pres gene and its effect on prestin function

Tóth¹,

Deák²,

Fazakas³

et al. 2007

Int J Mol Med

View full text Add to dashboard Cite

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“…Hair Cell Preparation and in Vitro Electrophysiology-Adult mice were euthanized with Euthasol (200 mg/kg), and OHCs were isolated as described previously (17). Whole-cell recordings were performed at room temperature using the Axopatch 200B amplifier (Molecular Devices, Sunnyvale, CA).…”

Section: Methodsmentioning

confidence: 99%

The V499G/Y501H Mutation Impairs Fast Motor Kinetics of Prestin and Has Significance for Defining Functional Independence of Individual Prestin Subunits

Homma

Duan

Zheng

et al. 2013

Journal of Biological Chemistry

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Background: Prestin converts electrical energy into mechanical work. Results: The V499G/Y501H mutation significantly impairs fast motor kinetics of prestin. Conclusion: Impaired kinetics is attributable to mutation at the Val-499 site that is conserved among SLC26 proteins regardless of their function as motors or transporters. Significance: V499G/Y501H mutated prestin provides clues to the molecular mechanisms underlying somatic electromotility and thus cochlear amplification.

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“…Adult mice were euthanized with euthasol, and OHCs were isolated in the same way as described before (13). Whole-cell recordings were performed at room temperature with holding potentials at 0 mV using the Axopatch 200B amplifier (Molecular Devices, Sunnyvale, CA).…”

Section: Methodsmentioning

confidence: 99%

Evidence That Prestin Has at Least Two Voltage-dependent Steps

Homma

Dallos

2011

Journal of Biological Chemistry

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Prestin is a voltage-dependent membrane-spanning motor protein that confers electromotility on mammalian cochlear outer hair cells, which is essential for normal hearing of mammals. Voltage-induced charge movement in the prestin molecule is converted into mechanical work; however, little is known about the molecular mechanism of this process. For understanding the electromechanical coupling mechanism of prestin, we simultaneously measured voltage-dependent charge movement and electromotility under conditions in which the magnitudes of both charge movement and electromotility are gradually manipulated by the prestin inhibitor, salicylate. We show that the observed relationships of the charge movement and the physical displacement (q-d relations) are well represented by a three-state Boltzmann model but not by a two-state model or its previously proposed variant. Here, we suggest a molecular mechanism of prestin with at least two voltage-dependent conformational transition steps having distinct electromechanical coupling efficiencies.Electromotility (1) of mammalian cochlear outer hair cells (OHCs) 2 is a rapid voltage-induced force-generating cell length change that is indispensable for the frequency selectivity and sensitivity of mammalian hearing (2). The membranebased motor protein, prestin, which is a member of the solute carrier 26 anion transporter family (3), is known to be responsible for generating electromotility (4). Accompanying OHC electromotility, charge movement in the lateral membrane of the cell is observed. This charge movement is manifested in the bell-shaped voltage-dependent cell membrane capacitance, which is often referred to as nonlinear capacitance (NLC) (5, 6)).The question of how prestin functions as a membranebased molecular motor has received a great deal of attention; however, even some fundamental issues are still obscure. To understand the mode of operation of the molecule, the relationship between charge movement, which initiates conformational change, and motor function needs to be quantified. However, only minimal attempts have been made to this effect (6, 7). Under normal operating circumstances NLC data are usually well explained by the simple two-state Boltzmann model with an apparent valency of charge of less than unity. Interesting theoretical work suggested that three-or higher-state models might provide superior description of the process (8, 9). In some work three-state fits were dictated by the data (10). To explain some properties of NLC at extreme membrane voltages, a modified two-state model has also been proposed (11). However, those models have not been subjected to rigorous examination as to their generality under various experimental conditions. It is one purpose of the present work to provide such an examination. We find that a Boltzmann model with at least two voltage-dependent steps is required for explaining prestin function.Since the discovery of prestin, assessments of effects of mutations and drugs on its function have become readily feasible using heter...

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Cochlear function in mice with only one copy of the prestin gene

Cited by 46 publications

References 48 publications

A new mutation in the human pres gene and its effect on prestin function

A new mutation in the human pres gene and its effect on prestin function

The V499G/Y501H Mutation Impairs Fast Motor Kinetics of Prestin and Has Significance for Defining Functional Independence of Individual Prestin Subunits

Evidence That Prestin Has at Least Two Voltage-dependent Steps

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