Die Rolle der Zusammensetzung der Zellmembran auf die mechanoelektrische Transduktion und Adaptation im Innenohr von Mamalia
Biologie des Verhaltens und der Sinne
Zusammenfassung der Projektergebnisse
During my DFG fellowship I investigated the importance of the cell membrane for the mammalian auditory mechano-electrical transduction (MET) channel. MET channels are essential to transfer mechanical stimuli, elicited by vibrations of the air and transferred to the inner ear, into electrical signal that our brain can understand. While the identity of several other MET channels is known, the auditory channel eludes identification. However, recording and characterizing the currents that are passed by the auditory MET channel allows us to deduce critical information about the workings of the channel, regardless of its molecular identity. Increasing our knowledge about how the auditory MET channel functions also increases our knowledge about how deafness can occur, how it could be prevented and could open new avenues for drug development. The auditory field was missing a closer investigation of the cell membrane/MET channel interaction, while other, non-auditory MET channels had been shown to depend on the correct lipid composition for functionality and sensitivity. For the auditory MET channel, I found that alterations of the cell membrane affect channel function and responses to mechanical stimuli. These data suggest that the auditory MET channel requires a specific lipid composition, controlling cell membrane stiffness, curvature, viscosity, and possibly single lipid molecules as cofactors. More specifically, I found that curvature alterations result in more MET channels being in their closed state compared to control conditions, while an increase of membrane area resulted in more channels being in their open state. This suggests that global membrane effects, such as curvature or viscosity, can affect channel function, implicating the cell membrane as a force relay element for the MET machinery. I also found that PIP2 is important for single MET channel properties, such as conductance, ion selectivity, and adaptation. The data from the PIP2 experiments suggests a more direct interaction of PIP2 with the MET channel proper or a closely associated protein. Taken together my data clearly shows for the first time that the mammalian, auditory MET channel depends on its lipid environment and closely interacts with it. These data will lay the foundation for further investigations and will ultimately help us to understand how the transfer of mechanical stimuli into electrical signals in the inner ear works.
Projektbezogene Publikationen (Auswahl)
- Designer aminoglycosides prevent cochlear hair cell loss and hearing loss. J Clin Invest. 2015 Feb; 125(2):583-92
Huth ME, Han KH, Sotoudeh K, Hsieh Y, Effertz T, Vu AA, Verhoeven S, Hsieh MH, Cheng AG, Ricci AJ
(Siehe online unter https://doi.org/10.1172/JCI77424) - Manipulations of Phosphatidylinositol 4,5-bisphosphate metabolism effects mechanoelectrical transduction currents in mammalian inner hair cells 52nd Annual Inner Ear Biology Workshop & Symposium, Rome 2015
Effertz T, Ricci AJ
- The how and why of identifying the hair cell mechanoelectrical transduction channel. Pflügers Archiv - European Journal of Physiology January 2015, Volume 467, Issue 1, pp 73-84
Effertz T, Scharr A, Ricci AJ
(Siehe online unter https://doi.org/10.1007/s00424-014-1606-z) - Loss of phosphoinositol-4,5-bisphospate reduces single channel conductance of mammalian inner hair cell MET-channels 53rd Workshop on Inner Ear Biology, Montpellier 2016
Effertz T, Becker L, Ricci AJ
- Phosphoinositol-4,5-bisphospate is required for normal cochlea hair cell function 39th Annual Midwinter Meeting of the Association for Research in Otolaryngology, San Diego 2016
Effertz T, Ricci AJ
