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1.A.75 The Mechanical Nociceptor, Piezo (Piezo) Family

Mechanical stimuli drive many physiological processes, including touch and pain sensation, hearing, and blood pressure regulation. Mechanically activated (MA) cation channel activities have been recorded in many cells. Coste et al. (2010) characterized a rapidly adapting MA current in a mouse neuroblastoma cell line. Expression profiling and RNA interference knockdown of candidate genes identified Piezo1 (Fam38A) to be required for MA currents in these cells. Piezo1 and related Piezo2 (Fam38B) are vertebrate multipass transmembrane proteins with homologs in invertebrates, plants, and protozoa. Overexpression of mouse Piezo1 or Piezo2 induced two kinetically distinct MA currents. Piezos are expressed in several tissues, and knockdown of Piezo2 in dorsal root ganglia neurons specifically reduced rapidly adapting MA currents. Coste et al. (2010) proposed that Piezos are components of MA cation channels.  Mouse piezo1 is involved in vacular system development, while piezo2 is concerned with touch sensitization (Coste et al. 2015). Ion-permeation properties are conferred by the C-terminal region, and a glutamate residue within a conserved region adjacent to the last two putative TMSs, when mutated, affects unitary conductance and ion selectivity, and modulates pore block (Coste et al. 2015).  Mutations in PIEZO2 contribute to Gordon syndrome, Marden-Walker syndrome and distal arthrogryposis, and a bioinformatics analysis of relevant mechanisms has appeared (Ma et al. 2019). Hereditary Xerocytosis (HX) is an autosomal dominantly inherited congenital hemolytic anemia associated with erythrocyte dehydration due to decreased intracellular potassium content resulting in increased mean corpuscular hemoglobin concentration. The affected members of HX families show compensated anemia with splenomegaly, hemosiderosis, and perinatal edema but are in large part transfusion independent. Functional studies show a link between mutations in mechanosensitive ion channel, encoded by PIEZO1 gene and the HX (de Meira Oliveira et al. 2020). The nematode, Caenorhabditis elegans has a single PIEZO ortholog (pezo-1) predicted to have 12 isoforms (Hughes et al. 2022). The Piezo1 ion channel is believed to play a role in glaucoma iinvolving mechanical stress (Chen et al. 2022). Land plant PIEZOs diverged from their animal homologs, both in function and subcellular localization, appearing to serve as vacuolar mecanosensors that promote membrane invagination in tip-growing cells (Radin et al. 2021).  The Piezo channel is central to the mechano-sensitive channel complex in the mammalian inner ear (Lee et al. 2023).

Ion channels have a role in neuronal mechanotransduction in invertebrates, but functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster and Caenorhabditis elegans, and it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans and potentially in D. melanogaster. However, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) are components of mechanically activated channels in mammals. Members of the Piezo family are evolutionarily conserved transmembrane proteins. Kim et al. (2012) studied the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression induces mechanically activated currents, similar to its mammalian counterparts. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Kim et al. (2012) found that Dmpiezo and ppk function in parallel pathways in ppk-positive cells, and that mechanical nociception is abolished in the absence of both channels. These data demonstrated the physiological relevance of the Piezo family in mechanotransduction in vivo, supporting a role of Piezo proteins in mechanosensory nociception. Membrane tension is not a mediator of long-range intracellular signaling, but local variations in tension mediate distinct processes in sub-cellular domains (Shi et al. 2018).

Piezo channels are ~2000 - 3000 aas long, have 34 - 42 TMSs, and appear to assemble into trimers, requiring no other proteins for activity. They have a reversal potential around 0 mV and show voltage dependent inactivation. The channel is constitutively active in liposomes, indicating that no cytoskeletal elements are required. Heterologous expression of the Piezo protein can create mechanical sensitivity in otherwise insensitive cells. Piezo1 currents in outside-out patches are blocked by the extracellular MSC inhibitor peptide GsMTx4. Both enantiomeric forms of GsMTx4 inhibited channel activity in a manner similar to endogenous mechanical channels. Piezo1 can adopt a tonic (non-inactivating) form with repeated stimulation. The transition to the non-inactivating form generally occurs in large groups of channels, indicating that the channels exist in domains, and once the domain is compromised, the members simultaneously adopt new properties. Piezo proteins are associated with physiological responses in cells, such as the reaction to noxious stimulus of Drosophila larvae. Piezo1 is also essential for the removal of extra cells without apoptosis. Piezo1 mutations have been linked to the pathological response of red blood cells in a genetic disease called Xerocytosis (Gottlieb and Sachs, 2012). MyoD (myoblast determination; Uniprot acc. # P15172; of 320 aas; also called BHLHC1, Myf3 and MYOD1) family inhibitor proteins (MDFIC and MDFI) are PIEZO1/2 interacting partners (Zhou et al. 2023). These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryoEM, the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module has been proposed (Zhou et al. 2023). 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.

Piezo homologues appear to consist of up to 9 (or sometimes 10) repeat domains, each with 4 TMSs. However at the C-termini of these proteins is an addition 3 or 4 TMSs in a DUF3595 domain. These proteins can be found in a wide range of eukaryotes (animals, plants, protozoa, slime molds, ciliates etc.) but not prokaryotes. Mouse Piezo1 (TC# 1.A.75.1.14) possesses a 38-transmembrane-helix topology with mechanotransduction components that enable a lever-like mechanogating mechanism, determined by cryoEM (Zhao et al. 2018). These channels may sense membrane tension through changes in the local curvature of the membrane (Liang and Howard 2018).  However, piezo channels are biochemically and functionally tethered to the actin cytoskeleton via the cadherin-beta-catenin mechanotransduction complex, whose perturbation impairs Piezo-mediated responses. Mechanistically, the adhesive extracellular domain of E-cadherin interacts with the cap domain of Piezo1, which controls the transmembrane gate, while its cytosolic tail might interact with the cytosolic domains of Piezo1, which are in close proximity to its intracellular gates, allowing a direct focus of adhesion-cytoskeleton-transmitted force for gating (Wang et al. 2022). Mulhall et al. 2023 observed the conformational dynamics of the blades of individual PIEZO1 molecules in a cell using nanoscopic fluorescence imaging. Compared with previous structural models of PIEZO1, the authors showed that the blades are significantly expanded at rest by the bending stress exerted by the plasma membrane. The degree of expansion varied dramatically along the length of the blade, where decreased binding strength between subdomains could explain increased flexibility of the distal blade. Using chemical and mechanical modulators of PIEZO1, Mulhall et al. 2023 showed that blade expansion and channel activation are correlated. Their findings help to uncover how PIEZO1 is activated in a native environment. 

Ge et al. 2015 determined the cryo-EM structure of the full-length (2,547 amino acids) mouse Piezo1 (Piezo1) at a resolution of 4.8 Å. Piezo1 forms a trimeric propeller-like structure (about 900 kilodaltons), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore (Ge et al. 2015). In the intracellular region, three long beam-like domains ( approximately 80Å in length) support the whole transmembrane region and connect the mobile peripheral regions to the central pore module. This design suggests that the trimeric mPiezo1 may mechanistically function by similar principles as how propellers sense and transduce force to control ion conductivity (Li et al. 2017). Local substrate stiffness is one of the major mechanical inputs for tissue organization during its development and remodeling. Epithelial cells sense local stiffness via Piezo1-mediated cytoskeletal reorganization (Jetta et al. 2023). The role of mechanosensitive ion channels in sexual behavior has been unveiled (George and Abraira 2023).

Piezo1 and Piezo2 mediate touch perception, proprioception and vascular development. Saotome et al. 2017 also reported a high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer. The detergent-solubilized complex adopts a three-blade propeller shape with a curved transmembrane region containing at least 26 TMSs per protomer. The flexible propeller blades can adopt distinct conformations and consist of a series of four-transmembrane helix 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 mouse Piezo1 possesses a 38-TMS topology with a central ion-conducting pore, three peripheral blade-like structures, and three 90-Å-long intracellular beam-resembling structures that bridge the blades to the pore. Wang et al. 2018 identified a set of Piezo1 chemical activators, termed Jedi, which activates Piezo1 through the extracellular side of the blade, indicating long-range allosteric gating. Jedi-induced activation requires the key mechanotransduction components, including the two extracellular loops in the distal blade and the two leucine residues in the proximal end of the beam. Thus, Piezo1 employs the peripheral blade-beam-constituted lever-like apparatus as a transduction pathway for long-distance mechano- and chemical-gating of the pore (Wang et al. 2018).

Piezo1 and Piezo2 assemble as transmembrane triskelions to combine exquisite force sensing with regulated calcium influx. They are important for endothelial shear stress sensing and secretion, Nitric oxide generation, vascular tone, angiogenesis, atherosclerosis, vascular permeability and remodeling, blood pressure regulation, insulin sensitivity, exercise performance, and baroreceptor reflex, and possibly the functioning of cardiac fibroblasts and myocytes. Human genetic analysis points to significance in lymphatic disease, anemia, varicose veins, and potentially heart failure, hypertension, aneurysms, and stroke. These channels appear to be versatile force sensors (Beech and Kalli 2019).

The Piezo1 channel is a key trabecular meshwork (TM) transducer of tensile stretch, shear flow and pressure. Its activation results in intracellular signals that alter organization of the cytoskeleton and cell-extracellular matrix contacts and modulate the trabecular component of aqueous outflow, whereas another channel, TRPV4, mediates a delayed mechanoresponse. TM mechanosensitivity utilizes kinetic, regulatory and functionally distinct pressure transducers to inform the cells about force-sensing. Piezo1 controls shear flow sensing, calcium homeostasis, cytoskeletal dynamics and pressure-dependent outflow (Yarishkin et al. 2020). Piezo1 channels have curved transmembrane domains, called arms, that create a convex membrane deformation, or footprint, which is predicted to flatten in response to increased membrane tension (Jiang et al. 2021). Due to the intrinsic bending rigidity of the membrane, the overlap of neighboring Piezo1 footprints produces a flattening of the Piezo1 footprints and arms. This tension-independent flattening is accompanied by gating motions that open an activation gate in the pore. This open state recapitulates experimentally obtained ionic selectivity, unitary conductance, and mutant phenotypes. Tracking ion permeation along the open pore reveals the presence of intracellular and extracellular fenestrations acting as cation-selective sites. Simulations also reveal multiple potential binding sites for phosphatidylinositol 4,5-bisphosphate (Jiang et al. 2021).

Structural designs and mechanogating mechanisms of Piezo channels have been reviewed (Jiang et al. 2021). Piezo channels, including Piezo1 and Piezo2 in mammals, serve as  mechanotransducers in various cell types and consequently governs fundamental pathophysiological processes ranging from vascular development to the sense of gentle touch and tactile pain. Piezo1/2 possesses a unique 38-TMS helix topology and forms a homotrimeric propeller-shaped structure comprising a central ion-conducting pore and three peripheral mechanosensing blades. The unusually curved TM region of the three blades shapes a signature nano-bowl configuration with the potential to generate large in-plane membrane area expansion, which might confer exquisite mechanosensitivity to Piezo channels. Jiang et al. 2021 reviewed the understanding of Piezo channels with a particular focus on their unique structural designs and elegant mechanogating mechanisms.

Membrane stretching causes Piezo1 to flatten and expand its blade region, resulting in tilting and lateral movement of the pore lining transmembrane helices 37 and 38 (De Vecchis et al. 2021). This is associated with opening of the channel and movement of lipids out of the pore region. Due to the rather loose packing of the Piezo1 pore region, movement of the lipids outside the pore region is critical for opening of the pore. Simulations suggest synchronous flattening of the Piezo1 blades during Piezo1 activation. The flattened structure lifts the C-terminal extracellular domain up, exposing it more to the extracellular space. Thus, it is the blade region of Piezo1 that senses tension in the membrane because pore opening failed in the absence of the blades. Upon opening, water molecules occupy lateral fenestrations in the cytosolic region of Piezo1 which might be likely paths for ion permeation (De Vecchis et al. 2021).

Mechanical cues are crucial for vascular development and the proper differentiation of various cell types. Piezo1 and Piezo2 are mechanically activated cationic channels expressed in various cell types, especially in vascular smooth muscle and endothelial cells (Shah et al. 2021). Each such protein is a homotrimeric complex that regulates calcium influx. Local blood flow associated shear stress, in addition to blood pressure associated cell membrane stretching are key Piezo channel activators. There is increasing evidence that piezo channels are significant in myocytes, cardiac fibroblast, vascular tone maintenance, atherosclerosis, hypertension, NO generation, and baroreceptor reflex. Shah et al. 2021 reviewed the role of Piezo channels in cardiovascular development and its associated clinical disorders, emphasizing piezo channel modulators. 

Radin et al. 2021 investigated PIEZO function in tip-growing cells in the moss Physcomitrium patens and the flowering plant Arabidopsis thaliana. PpPIEZO1 and PpPIEZO2 redundantly contribute to the normal growth, size, and cytoplasmic calcium oscillations of caulonemal cells. Both PpPIEZO1 and PpPIEZO2 localized to vacuolar membranes. Loss-of-function, gain-of-function, and overexpression mutants revealed that moss PIEZO homologs promote increased complexity of vacuolar membranes through tubulation, internalization, and/or fission. Arabidopsis PIEZO1 also localized to the tonoplast and is required for vacuole tubulation in the tips of pollen tubes. Radin et al. 2021 proposed that in plant cells, the tonoplast has more freedom of movement than the plasma membrane, making it a more effective location for mechanosensory proteins.

The transport reaction catalyzed by Piezo family members is: 

cations (in) ⇌ cations (out)

References associated with 1.A.75 family:

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