1.A.75.1.1
Piezo1 (FAM38a) mechanosensitive ion channel of 2521 aas and ~ 38 TMSs in a 4 x 9 + 2 TMS arrangement. The protein has a C-terminal DUF3595 (pfam 12166) domain (Coste et al., 2010).  Fam38A expression may cause increased cell migration and metastasis in lung tumours (McHugh et al. 2012). It is imporatnt for gastrointestinal tract function (Alcaino et al. 2017). A high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer has been determined (Saotome et al. 2017). The detergent-solubilized complex adopts a three-blade propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer. The flexible propeller blades can adopt distinct conformations, and consist of a series of four-TMS bundles termed 'Piezo repeats'. Carboxy-terminal domains line the central ion pore, and the channel is closed by constrictions in the cytosol. A kinked helical beam and anchor domain link the Piezo repeats to the pore, and are poised to control gating allosterically (Saotome et al. 2017). The Piezo1 pore remains fully open if only one subunit is activated, for example by binding the agonist, Yoda1 (Lacroix et al. 2018). The channel mediates uterine artery shear stress mechanotransduction and vasodilation during pregnancy (John et al. 2018). The channel can transport alkali monovalent cations (Na⁺, K⁺, Rb⁺, Cs⁺ and Li⁺ as well as Ca²⁺, tetramethyl ammonium and tetraethyl ammonium, although these last four cations are transported at slow rates (Gnanasambandam et al. 2017). Agonist-induced Piezo1 activation promotes mitochondrial-dependent apoptosis in vascular smooth muscle cells (Yin et al. 2022). Piezo1 is the stretch activated Ca²⁺ channel in red blood cells that mediates homeostatic volume control. Vaisey et al. 2022 studied the organization of Piezo1 in red blood cells. Piezo1 adopts a non-uniform distribution on the red blood cell surface, with a bias toward the biconcave 'dimple'. Trajectories of diffusing Piezo1 molecules, which exhibit confined Brownian diffusion on short timescales and hopping on long timescales, also reflect a bias toward the dimple. This bias can be explained by 'curvature coupling' between the intrinsic curvature of the Piezo dome and the curvature of the red blood cell membrane. Piezo1 does not form clusters with itself, nor does it colocalize with F-actin, Spectrin, or the Gardos channel. Thus, Piezo1 exhibits the properties of a force-through-membrane sensor of curvature and lateral tension in the red blood cell (Vaisey et al. 2022). Mechanosensitive Piezo1 channels trigger migraine pain in trigeminal nociceptive neurons (Della Pietra et al. 2023). Gain-of-function mutations in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis, an autosomal dominant hemolytic anemia characterized by high reticulocyte count, a tendency to macrocytosis, and mild jaundice, as well as by other variably penetrant clinical features, such as perinatal edema, severe thromboembolic complications after splenectomy, and hepatic iron overload (Andolfo et al. 2023). Mechanical stretching induces fibroblast apoptosis by activating Piezo1 and then destroying the actin cytoskeleton (Li et al. 2023). Force-induced motions of the PIEZO1 blade have been probed with fluorimetry (Ozkan et al. 2023). Low-intensity fluid shear stress causes a unique form of mechanical stress to the cell.  A light-gated mouse PIEZO1 channel, in which an azobenzene-based photoswitch covalently tethered to an engineered cysteine, Y2464C, localized at the extracellular apex of the TMS 38, rapidly triggers channel gating upon 365-nm-light irradiation. Peralta et al. 2023 provided evidence that this light-gated channel recapitulates mechanically-activated PIEZO1 functional properties, and show that light-induced molecular motions are similar to those evoked mechanically. GenEPi is a genetically-encoded fluorescent reporter for non-invasive optical monitoring of Piezo1-dependent activity. Yaganoglu et al. 2023 demonstrated that GenEPi has high spatiotemporal resolution for Piezo1-dependent stimuli from the single-cell level to that of the entire organism. GenEPi reveals transient, local mechanical stimuli in the plasma membrane of single cells, resolves repetitive contraction-triggered stimulation of beating cardiomyocytes within microtissues, and allows for robust and reliable monitoring of Piezo1-dependent activity in vivo (Yaganoglu et al. 2023). Membrane stretch provides a mechanism for activation of PIEZO1 channels in chondrocytes (Savadipour et al. 2023).  Zhou et al. 2023 found that MyoD (myoblast determination)-family inhibitor proteins (MDFIC and MDFI) are PIEZO1/2 interacting partners. These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryoEM, the authors mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These Piezo-interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous Piezo channels observed in many cell types, and elucidate mechanisms potentially involved in human lymphatic vascular disease (Zhou et al. 2023). PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K⁺ secretion (Carrisoza-Gaytan et al. 2024). The role and mechanism of PIEZO1 as a mechanical sensor in cardiovascular development, homeostasis, and disease processes, including embryo survival, angiogenesis, cardiac development repair, vascular inflammation, lymphangiogenesis, blood pressure regulation, cardiac hypertrophy, cardiac fibrosis, ventricular remodeling, and heart failure have been reviewed (Jin et al. 2024). Pain is one of the most severe manifestations in knee osteoarthritis (KOA) patients. The inflammatory response mediated by Piezo1 causes the release of inflammatory mediators and pro-inflammatory factors leading to pain (He et al. 2024).  Results suggest a previously unknown regulatory mechanism involving Piezo1 and influencing Glucagon-like peptide 1 (GLP-1) production in L epithelial cells,  could offer new insights into diabetes treatments (Huang et al. 2024). Loading directionality plays a role on PIEZO1 expression and the early-stage healing process of peri-implant bone (Mao et al. 2024). Piezo1 enhances macrophage phagocytosis and pyrin activation to ameliorate fungal keratitis (Yang et al. 2025). Mechanical stretch promotes the migration of mesenchymal stem cells via the Piezo1/F-actin/YAP axis (Ma et al. 2025).  Smooth muscle cell Piezo1 depletion results in impaired contractile properties in murine small bowel (Bautista et al. 2025). Piezo1 deletion mitigates diabetic cardiomyopathy by maintaining mitochondrial dynamics via the ERK/Drp1 pathway (Niu et al. 2025).  Endothelial Piezo1 stimulates angiogenesis to offer protection against intestinal ischemia-reperfusion injury in mice (Wang et al. 2025). Mechanical activation of adipose tissue macrophages mediated by Piezo1 protects against diet-induced obesity by regulating sympathetic activity (Leng et al. 2025).  A direct link between the loss of PIEZO1's mechanosensitivity and the pathophysiological phenotype of fetal hydrops raises the therapeutic potential of using PIEZO1 chemical activators to restore the mechanosensitivity of PIEZO1 missense mutants that are associated with genetic diseases such as GLD and hydrops fetalis (Jiang et al. 2025).  Cryo-light microscopy with angstrom precision has deciphered structural conformations of PIEZO1 in its native state (Mazal et al. 2025).  Piezo1 may play a role in heart failure because of its cytomechanical sensing to diverse cellular pathways (Wang et al. 2025).