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Hair bundle deflection generates a force by pulling on tip-link proteins connecting adjacent stereocilia. The resting open probability (<jats:italic>P<\/jats:italic><jats:sub>open<\/jats:sub>) of MET channels determines the linearity and sensitivity to mechanical stimulation. Classically,<jats:italic>P<\/jats:italic><jats:sub>open<\/jats:sub>is regulated by a calcium-sensitive adaptation mechanism in which lowering extracellular calcium or depolarization increases<jats:italic>P<\/jats:italic><jats:sub>open<\/jats:sub>. Recent data demonstrated that the fast component of adaptation is independent of both calcium and voltage, thus requiring an alternative explanation for the sensitivity of<jats:italic>P<\/jats:italic><jats:sub>open<\/jats:sub>to calcium and voltage. Using rat auditory hair cells, we characterize a mechanism, separate from fast adaptation, whereby divalent ions interacting with the local lipid environment modulate resting<jats:italic>P<\/jats:italic><jats:sub>open<\/jats:sub>. The specificity of this effect for different divalent ions suggests binding sites that are not an EF-hand or calmodulin model. GsMTx4, a lipid-mediated modifier of cationic stretch-activated channels, eliminated the voltage and divalent sensitivity with minimal effects on adaptation. We hypothesize that the dual mechanisms (lipid modulation and adaptation) extend the dynamic range of the system while maintaining adaptation kinetics at their maximal rates.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Classically, changes in extracellular calcium and voltage affect open probability (<jats:italic>P<\/jats:italic><jats:sub>open<\/jats:sub>) through mechanoelectric transduction adaptation, and this mechanism is the only means of controlling the set point of the channel. Here, we further characterize the effects of extracellular calcium and voltage on the channel and for the first time determine that these manipulations occur through a mechanism that is independent of fast adaptation and involves the lipid bilayer. These data additionally demonstrate that effects on<jats:italic>P<\/jats:italic><jats:sub>open<\/jats:sub>are not enough to characterize adaptation and thus may clarify some of the discrepancies within the literature as to mechanisms underlying adaptation.<\/jats:p>","DOI":"10.1523\/jneurosci.3011-15.2016","type":"journal-article","created":{"date-parts":[[2016,3,9]],"date-time":"2016-03-09T17:33:14Z","timestamp":1457544794000},"page":"2945-2956","source":"Crossref","is-referenced-by-count":66,"title":["Adaptation Independent Modulation of Auditory Hair Cell Mechanotransduction Channel Open Probability Implicates a Role for the Lipid Bilayer"],"prefix":"10.1523","volume":"36","author":[{"given":"Anthony 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