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PIEZO1

PIEZO1 is a mechanosensitive ion channel protein that in humans is encoded by the gene PIEZO1. PIEZO1 and its close homolog PIEZO2 were cloned in 2010, using an siRNA-based screen for mechanosensitive ion channels.[5]

PIEZO1
Identifiers
AliasesPIEZO1, DHS, FAM38A, Mib, LMPH3, piezo type mechanosensitive ion channel component 1, LMPHM6
External IDsOMIM: 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 MbChr 8: 123.21 – 123.28 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and function

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PIEZO1 (this gene) and PIEZO2 share 47% identity with each other and they have no similarity to any other protein and contain no known protein domains. 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.[6] 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. A lever-like mechanogating mechanism is assumed.[7][8]

 
Image of PIEZO1 homotrimer (left: from the side, right: from the top) created with PyMOL from PDB: 5Z10​.

Tissue distribution

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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.[5] Consequently PIEZO1 plays a significant role in multiple neurobiological processes including axon regeneration, neural stem cells differentiation and neurological diseases progression.[9]

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.[10][11][12]

Levels of PIEZO1 mRNA have been shown to be increased by mechanical stimulation, such as vibration at 1,000 Hz in monocytes.[13]

Clinical significance

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PIEZO1 is also found in red blood cells, and gain of function mutations in the channels are associated with hereditary xerocytosis or stomatocytosis.[14][15][16] PIEZO1 channels are pivotal integrators in vascular biology.[17]

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.[18]

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.[19]

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.[20]

Lymphatic malformation 6 syndrome is caused by mutations in PIEZO1 and was characterized in 2015.[21]

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.[22]

Ligands

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Agonists

Antagonists

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000103335 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ Monaco G, Lee B, Xu W, Mustafah S, Hwang YY, Carre C, Burdin N, Visan L, Ceccarelli M, Poidinger M, Zippelius A, Pedro de Magalhaes J, Larbi A (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.
  11. ^ Liu C, Raychaudhuri D, Paul B, Chakrabarty Y, Ghosh AR, Rahaman O, Talukdar A, Ganguly D (February 2018). "Cutting Edge: Piezo1 Mechanosensors Optimize Human T Cell Activation". J. Immunol. 200 (4): 1255–1260. doi:10.4049/jimmunol.1701118. PMID 29330322.
  12. ^ Jäntti H, Sitnikova V, Ishchenko Y, Shakirzyanova A, Giudice L, Ugidos IF, Gómez-Budia M, Korvenlaita N, Ohtonen S, Belaya I, Fazaludeen F, Mikhailov N, Gotkiewicz M, Ketola K, Lehtonen Š, Koistinaho J, Kanninen KM, Hernández D, Pébay A, Giugno R, Korhonen P, Giniatullin R, Malm T (June 2022). "Microglial Amyloid Beta Clearance is Driven by PIEZO1 Channels". J Neuroinflammation. 19 (1): 147. doi:10.1186/s12974-022-02486-y. PMC 9199162. PMID 35706029.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ Eisenhoffer GT, Loftus PD, Yoshigi M, Otsuna H, Chien CB, Morcos PA, Rosenblatt J (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.
  20. ^ 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.
  21. ^ 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.
  22. ^ Hu J, Chen Q, Zhu H, Hou L, Liu W, Yang Q, Shen H, Chai G, Zhang B, Chen S, Cai Z, Wu C, Hong F, Li H, Chen S (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. ISSN 0896-6273. PMID 36368316.
  23. ^ 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.
  24. ^ Bae C, Sachs F, Gottlieb PA (2011-07-26). "The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4". Biochemistry. 50 (29): 6295–6300. doi:10.1021/bi200770q. ISSN 0006-2960. PMC 3169095. PMID 21696149.
  25. ^ Gnanasambandam R, Ghatak C, Yasmann A, Nishizawa K, Sachs F, Ladokhin AS, Sukharev SI, Suchyna TM (2017-01-10). "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. ISSN 0006-3495. PMC 5231890. PMID 28076814.
  26. ^ Evans EL, Cuthbertson K, Endesh N, Rode B, Blythe NM, Hyman AJ, Hall SJ, Gaunt HJ, Ludlow MJ, Foster R, Beech DJ (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. ISSN 1476-5381. PMC 5913400. PMID 29498036.
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