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  • Piezo channels can be activated by

    2021-11-25

    Piezo channels can be activated by many mechanical stimuli . While some of these stimulations directly mimic physiological forces experienced by TUG 891 , such as shear stress applied in a microfluidic chamber, the most commonly used modes of stimulation consist of stretching the membrane by applying positive or negative pressure through a patch-clamp recording electrode or by poking the membrane using a blunt glass pipette. The main limitation of these techniques is that the amount of force required to gate Piezo channels cannot be accurately determined. Therefore, efforts are being made to develop other methods, such as stimulation with an atomic force microscopy cantilever to precisely quantify the force applied or the use of magnetic nanoparticles linked to the channel to apply localized pulling forces. Despite the limitations in pharmacological regulation of Piezo channels, a screen of more than three million compounds has now led to the identification of Yoda1, a synthetic small molecule that activates Piezo1 by lowering its mechanical sensitivity. Activation of Piezo channels generates cationic non-selective currents, these channels are permeant to monovalent cations, such as Na and K, and to divalent cations, such as Ca and Mg. Therefore, Piezos are excitatory channels, with their activation producing membrane depolarization. Piezo channel openings lead to Ca entry into the cell, potentially triggering intracellular Ca signaling pathways (). Piezo currents become inactivated during prolonged stimulations with relatively fast inactivation kinetics at negative potential (on a millisecond timescale) that tend to become slower as the membrane potential increases. Yes they are! Piezo2 is expressed in a subset of somatosensory neurons, the receptor cells that project throughout the whole body and are involved in the detection of touch, pain and proprioception. Since constitutive loss of induces perinatal lethality, the physiological role of Piezo2 in mechanosensation has been characterized using conditional deletion of in sensory neurons. These studies demonstrated a crucial role for Piezo2 in light-touch sensing as well as in proprioception, while ruling out its involvement in mechanical pain. Moreover, Piezo2 in vagal and spinal sensory neurons that innervate the respiratory system contributes to airway stretch sensing and mediates lung inflation-induced apnoea. Respiratory defects are therefore likely to be the cause of perinatal lethality in mice with constitutive loss of . Auditory hair cells contain TUG 891 mechanosensitive channels in their stereocilia that detect sound-induced vibrations. A recent study has shown that Piezo2 is expressed in these hair cells. However, Piezo2 is localized in the apical membrane of hair cells and is responsible for a reverse-polarity current but not for the sensory-transduction current. Also, its specific deletion in these cells only induces a mild auditory defect in mice. These results highlight the presence of at least two molecularly distinct mechanosensitive channels in auditory hair cells, among which Piezo2 is not the ‘hearing’ channel. The precise function of Piezo2 in hair cells therefore requires further characterization. Although Piezo1 has not been implicated so far in neuro-sensory functions, several studies have identified Piezo1 as a sensor of mechanical forces in endothelial, urothelial and renal epithelial cells. In particular, Piezo1 is involved in shear-stress sensing in blood vessel endothelial cells and is implicated in the developmental and physiological functions of the circulatory system, including the proper formation of blood vessels, regulation of vascular tone, and remodeling of small resistant arteries upon hypertension. The crucial role of Piezo1 in the development of the circulatory system explains the embryonic lethality of -deficient mice. In addition to its role in setting up and maintaining blood vessel integrity, Piezo1 is involved in red blood cell volume homeostasis. These cells experience significant mechanical forces while circulating in the bloodstream, and mechanosensitive Piezo1 channels act upstream of the calcium-activated potassium channel KCNN4 (also called the Gardos channel), which regulates intracellular cationic content and cell volume. Consequently, deletion in mice leads to overhydration of red blood cells.