Amphipathic molecules modulate PIEZO1 activity

PIEZO proteins are large eukaryotic mechanically-gated channels that function as homotrimers. The basic PIEZO1 structure has been elucidated by CryoEM and it assembles into a protein–lipid dome. A curved lipid region allows for the transition to the lipid bilayer from the dome (footprint). Gating PIEZO1 is mediated by bilayer tension that induces an area change in the lipid dome. The footprint region is thought to be energetically important for changes in lateral tension. Amphipathic molecules can modulate channel function beyond the intrinsic gating properties of PIEZO1. As a result, molecules that modify lipid properties within the lipid–channel complex (footprint and dome) will profoundly affect channel kinetics. In this review, we summarize the effects some amphipathic molecules have on the lipid bilayer and PIEZO1 function. PIEZO1 has three states, closed, open and inactivated and amphipathic molecules influence these transitions. The amphipathic peptide, GsMTx4, inhibits the closed to open transition. While saturated fatty acids also prevent PIEZO1 gating, the effect is mediated by stiffening the lipids, presumably in both the dome and footprint region. Polyunsaturated fatty acids can increase disorder within the lipid–protein complex affecting channel kinetics. PIEZO1 can also form higher-ordered structures that confers new kinetic properties associated with clustered channels. Cholesterol-rich domains house PIEZO1 channels, and depletion of cholesterol causes a breakdown of those domains with changes to channel kinetics and channel diffusion. These examples underscore the complex effects lipophilic molecules can have on the PIEZO1 lipid dome structure and thus on the mechanical response of the cell.

Control of hearing sensitivity by tectorial membrane calcium

When sound stimulates the stereocilia on the sensory cells in the hearing organ, Ca2+ions flow through mechanically gated ion channels. This Ca2+influx is thought to be important for ensuring that the mechanically gated channels operate within their most sensitive response region, setting the fraction of channels open at rest, and possibly for the continued maintenance of stereocilia. Since the extracellular Ca2+concentration will affect the amount of Ca2+entering during stimulation, it is important to determine the level of the ion close to the sensory cells. Using fluorescence imaging and fluorescence correlation spectroscopy, we measured the Ca2+concentration near guinea pig stereocilia in situ. Surprisingly, we found that an acellular accessory structure close to the stereocilia, the tectorial membrane, had much higher Ca2+than the surrounding fluid. Loud sounds depleted Ca2+from the tectorial membrane, and Ca2+manipulations had large effects on hair cell function. Hence, the tectorial membrane contributes to control of hearing sensitivity by influencing the ionic environment around the stereocilia.