Investigating the molecular mechanisms underlying touch in mice

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dc.contributor.advisor Hu, Jing (Dr.) Qi, Yanmei 2016-06-28T08:08:45Z 2016-06-28T08:08:45Z 2016-06
dc.identifier.other 472892479 de_DE
dc.identifier.uri de_DE
dc.description.abstract Although mechanosensation might be the most ancient one among our five senses, the mechanotransduction mechanism underlying the sense of touch remains to be least understood. A Stomatin like protein-3 (STOML3) has been shown to be essential for touch sensation in mouse. However, the molecular mechanisms by which STOML3 contribute to mechanotransduction remain elusive. In the first chapter of the thesis, we suggest a novel mechanism by which STOML3 modulates sensory mechanostransduction. STOML3, via binding cholesterol, controls membrane mechanics, thus facilitates the force transfer and tunes the sensitivity of the mechanically gated channels, including Piezo channels. Several lines of evidence support this conclusion. First, STOML3 is detected in cholesterol enriched lipid raft. Depletion of cholesterol and deficiency of STOML3 in sensory neurons similarly and interdependently affect membrane mechanics and attenuate mechanosensitivity. Second, we demonstrate that an intact STOML3 is essential for maintaining membrane mechanics to sensitize mechanically gated Piezo1 and Piezo2 channels in heterologous systems. Such a stiffened membrane can be softened by either depleting cholesterol or genetic disruption of cholesterol binding of STOML3. Third, mutation of residue involved in cholesterol binding (STOML-P40S) fails to modulate the sensitivity of Piezo channels or restore the mechanosensitivity of STOML3-/- sensory neurons. Finally, using a behavioral test, we show that cholesterol depletion could attenuate tactile allodynia and this effect involves STOML3. Factoring all these together, we propose that the stiffened membrane by STOML3 is essential for sensory mechanotransdution in vitro and the tactile sensitivity in vivo. STOML3 has been previously shown to interact with and inhibit the activity of Acid-sensing ion channels (ASICs). However, little is known about how this works. In the second chapter of the thesis, we examined whether STOML3 requires cholesterol-rich lipid rafts for regulating the activities of its associated ASIC channels. We show disrupting cholesterol-rich lipid rafts with Methyl-β-cyclodextrin robustly increases the proton-gated ASICs-like current in sensory neurons from C57BL/6N but not STOML3-/- mice, suggesting that the regulation of acid-sensing ion channels by lipid rafts involves STOML3 in sensory neurons. In heterologous expression cells, cholesterol depletion increases proton-gated ASICs-mediated currents and abolishes the inhibition of STOML3 on ASIC channel activity. Collectively, we suggest the regulation of ASIC channel by STOML3 requires the involvement of cholesterol-rich lipid rafts in mouse sensory neurons. In summary, with the above mentioned work, we would like to propose that binding cholesterol might be a general mechanism for STOML3 to regulate its associated ion channels including Piezos and ASICs. Touch evoked pain is the most common symptom of chronic pain and the effective treatment is absent. Our work on STOML3 would provide therapeutic opportunity for treating chronic pain. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri de_DE
dc.rights.uri en
dc.subject.classification Cholesterin , Maus de_DE
dc.subject.ddc 570 de_DE
dc.subject.ddc 610 de_DE
dc.subject.other Stomatin like protein-3 en
dc.subject.other Mechanostransduction en
dc.subject.other Cholesterol en
dc.subject.other Sensory neurons en
dc.title Investigating the molecular mechanisms underlying touch in mice en
dc.type Dissertation de_DE
dcterms.dateAccepted 2016-06-15
utue.publikation.fachbereich Interdisziplinäre Arbeitsgemeinschaften und Einrichtungen de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE


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