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Prestin is an anion transporter dispensable for mechanical feedback amplification in Drosophila hearing.

ABSTRACT: In mammals, the membrane-based protein Prestin confers unique electromotile properties to cochlear outer hair cells, which contribute to the cochlear amplifier. Like mammals, the ears of insects, such as those of Drosophila melanogaster, mechanically amplify sound stimuli and have also been reported to express Prestin homologs. To determine whether the D. melanogaster Prestin homolog (dpres) is required for auditory amplification, we generated and analyzed dpres mutant flies. We found that dpres is robustly expressed in the fly's antennal ear. However, dpres mutant flies show normal auditory nerve responses, and intact non-linear amplification. Thus we conclude that, in D. melanogaster, auditory amplification is independent of Prestin. This finding resonates with prior phylogenetic analyses, which suggest that the derived motor function of mammalian Prestin replaced, or amended, an ancestral transport function. Indeed, we show that dpres encodes a functional anion transporter. Interestingly, the acquired new motor function in the phylogenetic lineage leading to birds and mammals coincides with loss of the mechanotransducer channel NompC (=TRPN1), which has been shown to be required for auditory amplification in flies. The advent of Prestin (or loss of NompC, respectively) may thus mark an evolutionary transition from a transducer-based to a Prestin-based mechanism of auditory amplification.

SUBMITTER: Kavlie RG

PROVIDER: S-EPMC4282873 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Diverse Roles of Axonemal Dyneins in Drosophila Auditory Neuron Function and Mechanical Amplification in Hearing.

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Glutamate transporter homolog-based model predicts that anion-? interaction is the mechanism for the voltage-dependent response of prestin.

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Molecular mechanism of prestin electromotive signal amplification.

Project description:Hearing involves two fundamental processes: mechano-electrical transduction and signal amplification. Despite decades of studies, the molecular bases for both remain elusive. Here, we show how prestin, the electromotive molecule of outer hair cells (OHCs) that senses both voltage and membrane tension, mediates signal amplification by coupling conformational changes to alterations in membrane surface area. Cryoelectron microscopy (cryo-EM) structures of human prestin bound with chloride or salicylate at a common "anion site" adopt contracted or expanded states, respectively. Prestin is ensconced within a perimeter of well-ordered lipids, through which it induces dramatic deformation in the membrane and couples protein conformational changes to the bulk membrane. Together with computational studies, we illustrate how the anion site is allosterically coupled to changes in the transmembrane domain cross-sectional area and the surrounding membrane. These studies provide insight into OHC electromotility by providing a structure-based mechanism of the membrane motor prestin.

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Blood Prestin Levels in Normal Hearing and in Sensorineural Hearing Loss: A Scoping Review.

Project description:ObjectivesRecently, it has been hypothesized that blood prestin concentration levels may reflect cochlear damage and thus serve as an easily measurable, early sensorineural hearing loss (HL) biomarker. This is a scoping review aiming to identify and critically appraise current evidence on prestin blood levels and their temporal variation in rodents and humans with normal hearing and with sensorineural HL.DesignThis study was designed and held according to PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines. With no limitation with regards to study type, animal and human studies focusing on prestin blood levels in normal hearing and in sensorineural HL were sought in major databases such as Medline, Central Scopus, PROSPERO, and Clinicaltrials.gov. Results were then hand-searched. A data charting form was developed including the parameters of interest.ResultsSeven studies focusing on measuring prestin blood levels by means of ELISA in rodents and human subjects with normal hearing and noise-induced, drug-induced, or idiopathic sudden HL were found eligible and were included in the analysis. According to these proof-of-concept studies, prestin can be detected in the circulation of subjects with no HL; however, normal ranges remain unclear. After cochlear damage, blood prestin levels seem to initially rise and then return to near or below baseline. The degree of their change relates with subjects' degree of HL, damaged cochlear region and recovery. Prestin blood levels and their temporal variation seem to correlate with cochlear damage; however, methodological weaknesses, such as small sample size, lack of detailed phenotyping, insufficient exclusion of confounding factors, and short follow-up, do not allow for robust conclusions.ConclusionsCurrent findings support the value of studying blood prestin levels in normal hearing and HL and highlight a need for larger-scale longitudinal research.

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Nonmammalian orthologs of prestin (SLC26A5) are electrogenic divalent/chloride anion exchangers.

Project description:Individual members of the mammalian SLC26 anion transporter family serve two fundamentally distinct functions. Whereas most members transport different anion substrates across a variety of epithelia, prestin (SLC26A5) is special, functioning as a membrane-localized motor protein that generates electrically induced motions (electromotility) in auditory sensory hair cells of the mammalian inner ear. The transport mechanism of SLC26 proteins is not well understood, and a mechanistic relation between anion transport and electromotility has been suggested but not firmly established so far. To address these questions, we have cloned prestin orthologs from chicken and zebrafish, nonmammalian vertebrates that presumably lack electromotility in their auditory systems. Using patch-clamp recordings, we show that these prestin orthologs, but not mammalian prestin, generate robust transport currents in the presence of the divalent anions sulfate or oxalate. Transport is blocked by salicylate, an inhibitor of electromotility generated by mammalian prestin. The dependence of transport equilibrium potentials on sulfate and chloride concentration gradients shows that the prestin orthologs are electrogenic antiporters, exchanging sulfate or oxalate for chloride in a strictly coupled manner with a 1:1 stoichiometry. These data identify transport mode and stoichiometry of electrogenic divalent/monovalent anion exchange and establish a reliable and simple method for the quantitative determination of the various transport modes that have been proposed for other SLC26 transport proteins. Moreover, the sequence conservation between mammalian and nonmammalian prestin together with a common pharmacology of electromotility and divalent antiport suggest that the molecular mechanism behind electromotility is closely related to an anion transport cycle.

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Conformational state-dependent anion binding in prestin: evidence for allosteric modulation.

Project description:Outer hair cells boost auditory performance in mammals. This amplification relies on an expansive array of intramembranous molecular motors, identified as prestin, that drive somatic electromotility. By measuring nonlinear capacitance, the electrical signature of electromotility, we are able to assess prestin's conformational state and interrogate the effectiveness of anions on prestin's activity. We find that the affinity of anions depends on the state of prestin that we set with a variety of perturbations (in membrane tension, temperature, and voltage), and that movement into the expanded state reduces the affinity of prestin for anions. These data signify that anions work allosterically on prestin. Consequently, anions are released from prestin's binding site during expansion, i.e., during hyperpolarization. This is at odds with the extrinsic voltage sensor model, which suggests that prestin-bound intracellular anions are propelled deep into the membrane. Furthermore, we hypothesize that prestin's susceptibility to many biophysical forces, and notably its piezoelectric nature, may reflect anion interactions with the motor.

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