1.A.75.1.2
Piezo2 (FAM38b) of 2,752 aas and 37 TMSs in a 4 x 9 + 1 TMS arrangement. It is the major transducer of mechanical force for touch sensation (Ranade et al. 2014) and is a rapidly adapting mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors called Merkel cell neurite complexes.  Ranade et al. 2014 showed that touch and pain are mediated by distinct receptors. Piezo2 mediates alloknesis (pathological sensations including itch of dry skin (Feng et al. 2018). In fact, PIEZO2 is a mechanosensitive cation channel that plays a key role in sensing touch, tactile pain, breathing and blood pressure. Wang et al. 2019 described the cryo-EM structure of mouse PIEZO2, which is a three-bladed, propeller-like trimer that comprises 114 TMSs (38 per protomer). TMSs 1-36 (TM1-36) are folded into nine tandem units of four transmembrane helices each to form the unusual non-planar blades. The three blades are collectively curved into a nano-dome of 28-nm diameter and 10-nm depth, with an extracellular cap-like structure embedded in the centre and a 9-nm-long intracellular beam connecting to the central pore. TMS38 and the C-terminal domain are surrounded by the anchor domain and TMS37, and they enclose the central pore with both transmembrane and cytoplasmic constriction sites. Structural comparison between PIEZO2 and its homologue PIEZO1 revealed that the transmembrane constriction site might act as a gate that is controlled by the cap domain (Wang et al. 2019). Up-regulation of Piezo2 in the pain afferent neurons following trigeminal nerve injury may play a role in the development of neuralgia (Liu et al. 2021). Altering expression of the genes encoding Kv1.1, Piezo2, and TRPA1 regulate the response of mechanosensitive muscle nociceptors (Nagaraja et al. 2021). Intrinsically disordered intracellular domains control key features of the mechanically-gated ion channel PIEZO2 (Verkest et al. 2022). Human cutaneous mechanoreceptors can perform mechanotransduction already during embryonic development (García-Mesa et al. 2022). Genetic alterations of Piezo2 have been reported in human cancer (Liu et al. 2022). Piezo2 transmembrane excitatory mechanosensitive ion channels have been identified as the principal mechanotransduction channels for proprioception (Sonkodi 2022). Mechanical distension/stretch in the colon provokes visceral hypersensitivity and pain. Xie et al. reported that mechanosensitive Piezo2 channels, expressed by TRPV1-lineage nociceptors, are involved in visceral mechanical nociception and hypersensitivity (Xie et al. 2023). Zhou et al. 2023 found that MyoD (myoblast determination)-family inhibitor proteins (MDFIC (246 aas and 2 - 3 C-terminal TMSs 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).  PIEZO2 expression is an independent biomarker prognostic for gastric cancer and represents a potential therapeutic target (Zhang et al. 2024). Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity (Gabrielle et al. 2024). TMC7, a non-mechanosensitive TMC (TC# 1.A.17.4.18)), inhibits Piezo2-dependent mechanosensation (West and Schneider 2024).  Piezo2 is the principal mechanosensory ion channel responsible for proprioception, and acquired Piezo2 channelopathy is one principal gateway to pathophysiology (Sonkodi 2025).