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Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins.

ABSTRACT: Nature's fastest motors are the cochlear outer hair cells (OHCs). These sensory cells use a membrane protein, Slc26a5 (prestin), to generate mechanical force at high frequencies, which is essential for explaining the exquisite hearing sensitivity of mammalian ears. Previous studies suggest that Slc26a5 continuously diffuses within the membrane, but how can a freely moving motor protein effectively convey forces critical for hearing? To provide direct evidence in OHCs for freely moving Slc26a5 molecules, we created a knockin mouse where Slc26a5 is fused with YFP. These mice and four other strains expressing fluorescently labeled membrane proteins were used to examine their lateral diffusion in the OHC lateral wall. All five proteins showed minimal diffusion, but did move after pharmacological disruption of membrane-associated structures with a cholesterol-depleting agent and salicylate. Thus, our results demonstrate that OHC lateral wall structure constrains the mobility of plasma membrane proteins and that the integrity of such membrane-associated structures are critical for Slc26a5's active and structural roles. The structural constraint of membrane proteins may exemplify convergent evolution of cellular motors across species. Our findings also suggest a possible mechanism for disorders of cholesterol metabolism with hearing loss such as Niemann-Pick Type C diseases.

SUBMITTER: Yamashita T

PROVIDER: S-EPMC4564264 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins.

Yamashita Tetsuji T Hakizimana Pierre P Wu Siva S Hassan Ahmed A Jacob Stefan S Temirov Jamshid J Fang Jie J Mellado-Lagarde Marcia M Gursky Richard R Horner Linda L Leibiger Barbara B Leijon Sara S Centonze Victoria E VE Berggren Per-Olof PO Frase Sharon S Auer Manfred M Brownell William E WE Fridberger Anders A Zuo Jian J

PLoS genetics 20150909 9

Nature's fastest motors are the cochlear outer hair cells (OHCs). These sensory cells use a membrane protein, Slc26a5 (prestin), to generate mechanical force at high frequencies, which is essential for explaining the exquisite hearing sensitivity of mammalian ears. Previous studies suggest that Slc26a5 continuously diffuses within the membrane, but how can a freely moving motor protein effectively convey forces critical for hearing? To provide direct evidence in OHCs for freely moving Slc26a5 mo ...[more]

PMID: 26352669

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Project description:Outer hair cell (OHC) electromotility amplifies acoustic vibrations throughout the frequency range of hearing. Electromotility requires that the lateral membrane protein prestin undergo a conformational change upon changes in the membrane potential to produce an associated displacement charge. The magnitude of the charge displaced and the mid-reaction potential (when one half of the charge is displaced) reflects whether the cells will produce sufficient gain at the resting membrane potential to boost sound in vivo. Voltage clamp measurements performed under near-identical conditions ex vivo show the charge density and mid-reaction potential are not always the same, confounding interpretation of the results. We compare the displacement charge measurements in OHCs from rodents with a theory shown to exhibit good agreement with in silico simulations of voltage-sensing reactions in membranes. This model equates the charge density to the potential difference between two pseudo-equilibrium states of the sensors when they are in a stable conformation and not contributing to the displacement current. The model predicts this potential difference to be one half of its value midway into the reaction, when one equilibrium conformation transforms to the other pseudo-state. In agreement with the model, we find the measured mid-reaction potential to increase as the charge density decreases to exhibit a negative slope of ∼1/2. This relationship suggests that the prestin sensors exhibit more than one stable hyperpolarized state and that voltage sensing occurs by more than one pathway. We determine the electric parameters for prestin sensors and use the analytical expressions of the theory to estimate the energy barriers for the two voltage-dependent pathways. This analysis explains the experimental results, supports the theoretical approach, and suggests that voltage sensing occurs by more than one pathway to enable amplification throughout the frequency range of hearing.

Dataset Information

Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins.

Publications

Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins.

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