Hair Cells Require Phosphatidylinositol 4,5-Bisphosphate for Mechanical Transduction and Adaptation

Abstract

After opening in response to mechanical stimuli, hair cell transduction channels adapt with fast and slow mechanisms that each depend on Ca(2+). We demonstrate here that transduction and adaptation require phosphatidylinositol 4,5-bisphosphate (PIP(2)) for normal kinetics. PIP(2) has a striking distribution in hair cells, being excluded from the basal region of hair bundles and apical surfaces of frog saccular hair cells. Localization of a phosphatidylinositol lipid phosphatase, Ptprq, to these PIP(2)-free domains suggests that Ptprq maintains low PIP(2) levels there. Depletion of PIP(2) by inhibition of phosphatidylinositol 4-kinase or sequestration by aminoglycosides reduces the rates of fast and slow adaptation. PIP(2) and other anionic phospholipids bind directly to the IQ domains of myosin-1c, the motor that mediates slow adaptation, permitting a strong interaction with membranes and likely regulating the motor's activity. PIP(2) depletion also causes a loss in transduction current. PIP(2) therefore plays an essential role in hair cell adaptation and transduction.

Structure of the Single-lobe Myosin Light Chain C in Complex with the Light Chain-binding Domains of Myosin-1C Provides Insights into Divergent IQ Motif Recognition

“…This surface, which has a net positive charge and is relatively polar, is available for potential binding interactions with other cellular components. Mammalian myosin-1C is targeted to the tips of hair-cell stereocilia via its CaMbinding IQ motifs, which are exposed by the Ca 2ϩ -dependent release of CaM (34,35). It will be interesting to determine whether the LCBD plays a role in the localization of Dictyostelium myosin-1C.…”

Myosin-1A Targets to Microvilli Using Multiple Membrane Binding Motifs in the Tail Homology 1 (TH1) Domain

“…Although the labeling methods used here show that PS and PI(4,5)P 2 are both found in microvilli, it is still unclear if these lipids compartmentalize into subdomains along the microvillar axis. In bullfrog saccular hair cells, PI(4,5)P 2 is found strictly at the tips of stereocilia, whereas PS is more widely distributed along the length of these protrusions (50). If such compartmentalization of lipid species is found in microvilli, it could provide one possible mechanism for polarizing the distribution of membrane-associated proteins throughout this structure.…”

The Transduction Channel Filter in Auditory Hair Cells

“…One possibility is that MET channels in mammalian cochlear hair cells contain a different set of ␣ subunit isoforms from those used in the turtle or that the properties are modified by another accessory ␤ subunit. The local environment for the channel may also differ: membrane lipids such as phosphatidylinositol 4,5-bisphosphate can alter the time course of adaptation (Hirono et al 2004) so may also affect activation. A third possibility is that the mechanical coupling to the channel, for example the gating springs, may differ in some way.…”