PIEZO1

Last updated

PIEZO1
Identifiers
Aliases PIEZO1 , DHS, FAM38A, Mib, LMPH3, piezo type mechanosensitive ion channel component 1, LMPHM6
External IDs OMIM: 611184; MGI: 3603204; HomoloGene: 124356; GeneCards: PIEZO1; OMA:PIEZO1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9780

234839

Ensembl

ENSG00000103335

ENSMUSG00000014444

UniProt

Q92508

E2JF22

RefSeq (mRNA)

NM_001142864

NM_001037298
NM_001357349

RefSeq (protein)

NP_001136336

n/a

Location (UCSC) Chr 16: 88.72 – 88.79 Mb Chr 8: 123.21 – 123.28 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Piezo-type mechanosensitive ion channel component 1 is a protein that in humans is encoded by the PIEZO1 gene. [5] PIEZO1 is a large mechanosensitive ion channel protein that forms a homotrimeric complex with a distinctive three-bladed, propeller-shaped architecture. Each subunit of PIEZO1 contains between 30 and 40 transmembrane domains. The protein consists of a central pore module and peripheral mechanotransduction modules. The pore module is composed of the last two transmembrane helices, an extracellular cap domain, and an intracellular C-terminal domain. [6] [7]

Contents

PIEZO1 functions as a non-selective cation channel capable of conducting both monovalent and divalent cations, including Na+, K+, and Ca2+. The mechanosensitivity of PIEZO1 is a defining characteristic. It can be directly activated by membrane tension, with the peripheral blade and beam structures likely acting as mechanotransduction modules. Notably, PIEZO1 requires lower tension for activation compared to bacterial mechanosensitive channels. The protein exhibits voltage-dependent inactivation. PIEZO1 serves as a mechanotransducer in various cell types and tissues playing roles in processes such as vascular development, red blood cell volume regulation, and epithelial homeostasis. [8]

Piezo1 and its close homolog Piezo2 were cloned in 2010, using an siRNA-based screen for mechanosensitive ion channels. [9]

Structure

Image of PIEZO1 homotrimer (left: from the side, right: from the top) from PDB: 5Z10 . Piezo1 homotrimer.png
Image of PIEZO1 homotrimer (left: from the side, right: from the top) from PDB: 5Z10 ​.

Piezo1 (this gene) and Piezo2 share 47% identity with each other and they have no similarity to any other protein, making them unique among ion channels. They are predicted to have 24-36 transmembrane domains, depending on the prediction algorithm used. In the original publication the authors were careful not to call the piezo proteins ion channels, but a more recent study by the same lab convincingly demonstrated that indeed Piezo1 is the pore-forming subunit of a mechanosensitive channel. [10] This new "Piezo" family is catalogued as InterPro :  IPR027272 and TCDB 1.A.75 . Piezo1 homologues are found in C. elegans and Drosophila , which, like other invertebrates, have a single Piezo protein.

It is known ( PDB: 6B3R ​) that Piezo1 channel is a three-bladed propeller-like structure, or trimer, with unique membrane curvature. When activated, a lever-like mechanogating mechanism is assumed for the flexible blades, opening the central pore to allow for the influx of calcium ions. [6] [11] Typically, this is in response to mechanical tension and ultimately leads to the triggering of downstream signaling pathways. As such, Piezo1 activation is essential to transduction of biochemical signals.

Function

Cell volume regulation

Regulatory Volume Decrease by Piezo1 made with BioRender Regulatory Volume Decrease by Piezo1.png
Regulatory Volume Decrease by Piezo1 made with BioRender

Mechanotransduction refers to cellular responses that arise from the conversion of mechanical stimuli. Piezo1 plays a critical role in maintaining cell volume, especially under osmotic stress. It senses membrane stretches after swelling due to hypotonic conditions and mediates calcium-dependent activation of volume-regulated anion channels (VRACs) and Kca channels, initiating a process known as regulatory volume decrease (RVD) to help cells recover their original size. [12] Potassium and chloride ions are expelled in this process to restore osmotic balance, creating a gradient that encourages water to move out of the cell. This prevents cellular damage from prolonged swelling and is particularly important for cellular homeostasis, as Piezo1 modulates the ionic efflux and water movement. This mechanism is highlighted in erythrocytes, where volume changes in narrow capillaries can lead to hemolysis. Piezo1 activation supports the structural integrity and adaptation of these cells to maintain efficient oxygen transport. [13]

Cell cycle regulation and migration

The influx of calcium ions induces changes in membrane potential and intracellular ion concentration, leading to a cascade of signaling pathways. These activate calcium-dependent kinases and cascades like the ERK1/2 branch of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is well characterized and plays a role in regulating a variety of cellular processes. In the ERK1/2 branch, Piezo1-mediated calcium influx phosphorylates downstream targets, regulating gene expression and cell cycle progression, especially in periodontal ligament cells (PDLCs) where tissue remodeling is prominent. [12] [14]

Hippo/Yap Function The essential physiological function of Hippo pathway.webp
Hippo/Yap Function

In dorsal root ganglia (DRG), Piezo1 enables cells to detect substrate stiffness and modulate behavior through the calpain-integrin-E-cadherin pathway. [15] Beginning with the activation of calpain, a protease that modulates the cytoskeleton and E-cadherin, this pathway affects integrin B1, a receptor of extracellular matrix proteins. Piezo1 signaling ensures the proper localization to facilitate cell-matrix adhesion, cellular aggregation, and balance between proliferation with apoptosis. In endothelial cells, this homeostasis supports vascular development because integrins are crucial for angiogenesis. [13] [16]

Additionally, Piezo1 can affect the Hippo/YAP pathway, which controls cell proliferation and differentiation, underscoring Piezo1’s role in cellular metastasis. In ovarian cancer, Piezo1 facilitates nuclear translocation of YAP and promotes the epithelial-to-mesenchymal transition (EMT), which leads to acquisition of invasive characteristics and is a hallmark of cancer metastasis. The promotion of EMT enhances the migratory capabilities of cancer cells. [17] With this knowledge, further research is needed to investigate the inhibition of tumor progression that therapeutic targeting potentially offers.

Regulation

Conformational signaling

Membrane Curvature in Different States of Piezo1 (made with BioRender) Membrane Curvature in Piezo1.png
Membrane Curvature in Different States of Piezo1 (made with BioRender)

Piezo1 also engages in conformational signaling and influences nearby proteins due to changes in its membrane curvature. [18] The influence extends tens of nanometers from Piezo1, affecting the surrounding lipid bilayer. This mechanism is independent from direct protein interaction, but is still critical in modulating local ion channels and signaling cascades. [12] [18] Interactions with TREK1 potassium channels are a prime example of this relationship. TREK1 is a two-pore channel that similarly responds to mechanical stimuli. Activation of Piezo1 enhances TREK1 activity through modulating its gating properties with greater amplitude and prolonged activation state, even in the absence of ion flow through Piezo1. Research has found that these do not colocalize, meaning there are no direct physical interactions between them. [18]

Feedback mechanisms

Self-Limiting Mechanism of Piezo1 (made with BioRender) Relationship between PLCs, PIP2, and Piezo1.png
Self-Limiting Mechanism of Piezo1 (made with BioRender)

Increased intracellular calcium also activates phospholipase C (PLC), in turn hydrolyzing PIP2. The hydrolysis of PIP2 directly affects Piezo1 activity. [14] A self-limiting mechanism of Piezo1 is activity reduction caused by depletion of PIP2 in the membrane. This ensures that Piezo1 does not remain excessively active.

Tissue distribution

Piezo1 is expressed in the lungs, bladder and skin, where mechanosensation has important biological roles. Unlike Piezo2 which is highly expressed in sensory dorsal root ganglia, Piezo1 is not expressed in sensory neurons. [9] Consequently Piezo1 plays a significant role in multiple neurobiological processes including axon regeneration, neural stem cells differentiation and neurological diseases progression. [19]

Piezo1 is also expressed in immune cells, including lymphocytes and myeloid cells, and has been shown to have a role in the function of fundamental immune processes, like antigen presentation and phagocytosis. [20] [21] [22]

Levels of Piezo1 mRNA have been shown to be increased by mechanical stimulation, such as vibration at 1,000 Hz in monocytes. [23]

Clinical significance

Piezo1 is also found in red blood cells, and gain of function mutations in the channels are associated with hereditary xerocytosis or stomatocytosis. [24] [25] [26] Piezo1 channels are pivotal integrators in vascular biology. [27]

An allele of Piezo1, E756del, results in a gain-of-function mutation, resulting in dehydrated RBCs and conveying resistance to Plasmodium . This allele has been demonstrated in vitro to prevent cerebral malaria infection. [28]

Piezo1 has been implicated in extrusion of epidermal cells when a layer becomes too confluent to preserve normal skin homeostasis. This acts to prevent excess proliferation of skin tissue, and has been implicated in cancer biology as a contributing factor to metastases by assisting living cells in escaping from a monolayer. [29]

Expression of murine Piezo1 in mouse innate immune cells is essential for their function, a role mediated by sensing mechanical cues. Deficiency in Piezo1 in mice lead to increased susceptibility of myeloid cells to infection by Pseudomonas aeruginosa . [30]

Lymphatic malformation 6 syndrome is caused by mutations in Piezo1 and was characterized in 2015. [31]

Piezo1 has been proposed as a therapeutic target for Alzheimer's disease. The build-up of amyloid-β plaques stiffen the brain's structure. Microglial maintenance cells, which express Piezo1, detect this stiffness via Piezo1-enabled mechanosensation and in response surround, compact, and phagocytosize the plaques. Removal of the gene which codes for Piezo1 in microglia decreases plaque clearance and hastens cognitive decline in rats. [32]

Ligands

Agonists

Antagonists

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000103335 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000014444 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Lai A, Cox CD, Chandra Sekar N, Thurgood P, Jaworowski A, Peter K, et al. (April 2022). "Mechanosensing by Piezo1 and its implications for physiology and various pathologies". Biological Reviews of the Cambridge Philosophical Society. 97 (2): 604–614. doi:10.1111/brv.12814. PMID   34781417.
  6. 1 2 Zhao Q, Zhou H, Li X, Xiao B (July 2019). "The mechanosensitive Piezo1 channel: a three-bladed propeller-like structure and a lever-like mechanogating mechanism". The FEBS Journal. 286 (13): 2461–2470. doi:10.1111/febs.14711. PMID   30500111.
  7. ↑ Wang Y, Xiao B (March 2018). "The mechanosensitive Piezo1 channel: structural features and molecular bases underlying its ion permeation and mechanotransduction". The Journal of Physiology. 596 (6): 969–978. doi:10.1113/JP274404. PMC   5851880 . PMID   29171028.
  8. ↑ Nosyreva ED, Thompson D, Syeda R (2021). "Identification and functional characterization of the Piezo1 channel pore domain". The Journal of Biological Chemistry. 296: 100225. doi: 10.1074/jbc.RA120.015905 . PMC   7948955 . PMID   33361157.
  9. 1 2 Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, et al. (October 2010). "Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels". Science. 330 (6000): 55–60. Bibcode:2010Sci...330...55C. doi:10.1126/science.1193270. PMC   3062430 . PMID   20813920.
  10. ↑ Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, et al. (February 2012). "Piezo proteins are pore-forming subunits of mechanically activated channels". Nature. 483 (7388): 176–181. Bibcode:2012Natur.483..176C. doi:10.1038/nature10812. PMC   3297710 . PMID   22343900.
  11. ↑ Wang Y, Chi S, Guo H, Li G, Wang L, Zhao Q, et al. (April 2018). "A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel". Nature Communications. 9 (1): 1300. Bibcode:2018NatCo...9.1300W. doi:10.1038/s41467-018-03570-9. PMC   5880808 . PMID   29610524.
  12. 1 2 3 Shen Y, Pan Y, Guo S, Sun L, Zhang C, Wang L (May 2020). "The roles of mechanosensitive ion channels and associated downstream MAPK signaling pathways in PDLC mechanotransduction". Molecular Medicine Reports. 21 (5): 2113–2122. doi:10.3892/mmr.2020.11006. PMC   7115221 . PMID   32323761.
  13. 1 2 Michelucci A, Catacuzzeno L (July 2024). "Piezo1, the new actor in cell volume regulation". Pflügers Archiv. 476 (7): 1023–1039. doi:10.1007/s00424-024-02951-y. PMC   11166825 . PMID   38581527.
  14. 1 2 Borbiro I, Rohacs T (2017). "Regulation of Piezo Channels by Cellular Signaling Pathways". Current Topics in Membranes. 79. Elsevier: 245–261. doi:10.1016/bs.ctm.2016.10.002. ISBN   978-0-12-809389-4. PMC   6464384 . PMID   28728819.
  15. ↑ Lei M, Wang W, Zhang H, Gong J, Wang Z, Cai H, et al. (December 2023). "Cell-cell and cell-matrix adhesion regulated by Piezo1 is critical for stiffness-dependent DRG neuron aggregation". Cell Reports. 42 (12): 113522. doi: 10.1016/j.celrep.2023.113522 . PMID   38048221.
  16. ↑ Sugimoto A, Iwata K, Kurogoushi R, Tanaka M, Nakashima Y, Yamakawa Y, et al. (November 2023). "C-terminus of PIEZO1 governs Ca2+ influx and intracellular ERK1/2 signaling pathway in mechanotransduction". Biochemical and Biophysical Research Communications. 682: 39–45. doi: 10.1016/j.bbrc.2023.09.080 . PMID   37801988.
  17. ↑ Xiong Y, Dong L, Bai Y, Tang H, Li S, Luo D, et al. (December 2022). "Piezo1 activation facilitates ovarian cancer metastasis via Hippo/YAP signaling axis". Channels. 16 (1): 159–166. doi:10.1080/19336950.2022.2099381. PMC   9367648 . PMID   35942515.
  18. 1 2 3 Lewis AH, Cronin ME, Grandl J (September 2024). "Piezo1 ion channels are capable of conformational signaling". Neuron. 112 (18): 3161–3175.e5. doi:10.1016/j.neuron.2024.06.024. PMC  11427155. PMID   39043183.
  19. ↑ Bryniarska-Kubiak N, Kubiak A, Basta-Kaim A (October 2023). "Mechanotransductive Receptor Piezo1 as a Promising Target in the Treatment of Neurological Diseases". Current Neuropharmacology. 21 (10): 2030–2035. doi:10.2174/1570159X20666220927103454. PMC   10556366 . PMID   36173070.
  20. ↑ Monaco G, Lee B, Xu W, Mustafah S, Hwang YY, Carré C, et al. (February 2019). "RNA-Seq Signatures Normalized by mRNA Abundance Allow Absolute Deconvolution of Human Immune Cell Types". Cell Reports. 26 (6): 1627–1640.e7. doi:10.1016/j.celrep.2019.01.041. PMC   6367568 . PMID   30726743.
  21. ↑ Liu CS, Raychaudhuri D, Paul B, Chakrabarty Y, Ghosh AR, Rahaman O, et al. (February 2018). "Cutting Edge: Piezo1 Mechanosensors Optimize Human T Cell Activation". Journal of Immunology. 200 (4): 1255–1260. doi:10.4049/jimmunol.1701118. PMID   29330322.
  22. ↑ Jäntti H, Sitnikova V, Ishchenko Y, Shakirzyanova A, Giudice L, Ugidos IF, et al. (June 2022). "Microglial amyloid beta clearance is driven by PIEZO1 channels". Journal of Neuroinflammation. 19 (1): 147. doi: 10.1186/s12974-022-02486-y . PMC   9199162 . PMID   35706029.
  23. ↑ Simakou T, Freeburn R, Henriquez FL (July 2021). "Gene expression during THP-1 differentiation is influenced by vitamin D3 and not vibrational mechanostimulation". PeerJ. 9: e11773. doi: 10.7717/peerj.11773 . PMC   8286059 . PMID   34316406.
  24. ↑ Zarychanski R, Schulz VP, Houston BL, Maksimova Y, Houston DS, Smith B, et al. (August 2012). "Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis". Blood. 120 (9): 1908–1915. doi:10.1182/blood-2012-04-422253. PMC   3448561 . PMID   22529292.
  25. ↑ Bae C, Gnanasambandam R, Nicolai C, Sachs F, Gottlieb PA (March 2013). "Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1". Proceedings of the National Academy of Sciences of the United States of America. 110 (12): E1162 –E1168. Bibcode:2013PNAS..110E1162B. doi: 10.1073/pnas.1219777110 . PMC   3606986 . PMID   23487776.
  26. ↑ Albuisson J, Murthy SE, Bandell M, Coste B, Louis-Dit-Picard H, Mathur J, et al. (2013). "Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels". Nature Communications. 4: 1884. Bibcode:2013NatCo...4.1884A. doi:10.1038/ncomms2899. PMC   3674779 . PMID   23695678.
  27. ↑ Li J, Hou B, Tumova S, Muraki K, Bruns A, Ludlow MJ, et al. (November 2014). "Piezo1 integration of vascular architecture with physiological force". Nature. 515 (7526): 279–282. Bibcode:2014Natur.515..279L. doi:10.1038/nature13701. PMC   4230887 . PMID   25119035.
  28. ↑ Ma S, Cahalan S, LaMonte G, Grubaugh ND, Zeng W, Murthy SE, et al. (April 2018). "Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection". Cell. 173 (2): 443–455.e12. doi:10.1016/j.cell.2018.02.047. PMC   5889333 . PMID   29576450.
  29. ↑ Eisenhoffer GT, Loftus PD, Yoshigi M, Otsuna H, Chien CB, Morcos PA, et al. (April 2012). "Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia". Nature. 484 (7395): 546–549. Bibcode:2012Natur.484..546E. doi:10.1038/nature10999. PMC   4593481 . PMID   22504183.
  30. ↑ Solis AG, Bielecki P, Steach HR, Sharma L, Harman CC, Yun S, et al. (September 2019). "Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity". Nature. 573 (7772): 69–74. Bibcode:2019Natur.573...69S. doi:10.1038/s41586-019-1485-8. PMC   6939392 . PMID   31435009.
  31. ↑ Fotiou E, Martin-Almedina S, Simpson MA, Lin S, Gordon K, Brice G, et al. (September 2015). "Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis". Nature Communications. 6: 8085. Bibcode:2015NatCo...6.8085F. doi:10.1038/ncomms9085. PMC   4568316 . PMID   26333996.
  32. ↑ Hu J, Chen Q, Zhu H, Hou L, Liu W, Yang Q, et al. (January 2023). "Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease". Neuron. 111 (1): 15–29.e8. doi: 10.1016/j.neuron.2022.10.021 . PMID   36368316.
  33. ↑ Syeda R, Xu J, Dubin AE, Coste B, Mathur J, Huynh T, et al. (May 2015). "Chemical activation of the mechanotransduction channel Piezo1". eLife. 4. doi: 10.7554/eLife.07369 . PMC   4456433 . PMID   26001275.
  34. ↑ Bae C, Sachs F, Gottlieb PA (July 2011). "The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4". Biochemistry. 50 (29): 6295–6300. doi:10.1021/bi200770q. PMC   3169095 . PMID   21696149.
  35. ↑ Gnanasambandam R, Ghatak C, Yasmann A, Nishizawa K, Sachs F, Ladokhin AS, et al. (January 2017). "GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels". Biophysical Journal. 112 (1): 31–45. Bibcode:2017BpJ...112...31G. doi:10.1016/j.bpj.2016.11.013. PMC   5231890 . PMID   28076814.
  36. ↑ Evans EL, Cuthbertson K, Endesh N, Rode B, Blythe NM, Hyman AJ, et al. (May 2018). "Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation". British Journal of Pharmacology. 175 (10): 1744–1759. doi:10.1111/bph.14188. PMC   5913400 . PMID   29498036.
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