Piezo Proteins Research Articles

Localization of Piezo 1 and Piezo 2 in Lateral Line System and Inner Ear of Zebrafish (Danio rerio).

Piezo proteins have been identified as mechanosensitive ion channels involved in mechanotransduction. Several ion channel dysfunctions may be associated with diseases (including deafness and pain); thus, studying them is critical to understand their role in mechanosensitive disorders and to establish new therapeutic strategies. The current study investigated for the first time the expression patterns of Piezo proteins in zebrafish octavolateralis mechanosensory organs. Piezo 1 and 2 were immunoreactive in the sensory epithelia of the lateral line system and the inner ear. Piezo 1 (28.7 ± 1.55 cells) and Piezo 2 (28.8 ± 3.31 cells) immunopositive neuromast cells were identified based on their ultrastructural features, and their overlapping immunoreactivity to the s100p specific marker (28.6 ± 1.62 cells), as sensory cells. These findings are in favor of Piezo proteins' potential role in sensory cell activation, while their expression on mantle cells reflects their implication in the maintenance and regeneration of the neuromast during cell turnover. In the inner ear, Piezo proteins' colocalization with BDNF introduces their potential implication in neuronal plasticity and regenerative events, typical of zebrafish mechanosensory epithelia. Assessing these proteins in zebrafish could open up new scenarios for the roles of these important ionic membrane channels, for example in treating impairments of sensory systems.

Mechanisms controlling haemolymph circulation under resting conditions in the Chagas disease vector Rhodnius prolixus.

Chagas disease vectors can ingest several times their own volume in blood with each meal. This ad libitum feeding causes an intense process of diuresis, inducing the insect to eliminate a large quantity of urine and faeces. To ensure diuresis, the speed of circulation of the haemolymph is increased. The Triatominae circulatory system is quite simple, including the dorsal vessel, which pumps haemolymph in an anterograde direction. The return is caused by peristaltic contractions of the anterior midgut. Triatominae insects can spend several weeks without feeding, meaning that most of the time, the insect is in a resting condition. Although the mechanisms controlling the circulation of the haemolymph during post-prandial diuresis have been largely analysed, the mechanisms controlling it during resting conditions are poorly understood. In this study, we analysed several canonical pathways (i.e. L-type VGCC, GPCR, RyR, IP3R) and a novel system represented by the recently characterized Piezo proteins. Our results show that during the resting condition, haemolymph circulation depends on a cross-talk between myogenic activity, inhibitory and stimulatory cellular messengers, and Piezo proteins. This report also unveils for the first time the existence of a putative Piezo protein in Hemiptera.

Piezo 1 and Piezo 2 in the Chemosensory Organs of Zebrafish (Danio rerio).

The ion channels Piezo 1 and Piezo 2 have been identified as membrane mechano-proteins. Studying mechanosensitive channels in chemosensory organs could help in understanding the mechanisms by which these channels operate, offering new therapeutic targets for various disorders. This study investigates the expression patterns of Piezo proteins in zebrafish chemosensory organs. For the first time, Piezo protein expression in adult zebrafish chemosensory organs is reported. In the olfactory epithelium, Piezo 1 immunolabels kappe neurons, microvillous cells, and crypt neurons, while Calretinin is expressed in ciliated sensory cells. The lack of overlap between Piezo 1 and Calretinin confirms Piezo 1's specificity for kappe neurons, microvillous cells, and crypt neurons. Piezo 2 shows intense immunoreactivity in kappe neurons, one-ciliated sensory cells, and multi-ciliated sensory cells, with overlapping Calretinin expression, indicating its olfactory neuron nature. In taste buds, Piezo 1 immunolabels Merkel-like cells at the bases of cutaneous and pharyngeal taste buds and the light and dark cells of cutaneous and oral taste buds. It also marks the dark cells of pharyngeal taste buds and support cells in oral taste buds. Piezo 2 is found in the light and dark cells of cutaneous and oral taste buds and isolated chemosensory cells. These findings provide new insights into the distribution of Piezo channels in zebrafish chemosensory organs, enhancing our understanding of their sensory processing and potential therapeutic applications.

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

Roles of the mechanosensitive ion channel Piezo1 in the renal podocyte injury of experimental hypertensive nephropathy.

Glomerular podocyte injury plays an essential role in proteinuria pathogenesis, a hallmark of chronic kidney disease, including hypertensive nephropathy. Although podocytes are susceptible to mechanical stimuli, their mechanotransduction pathways remain elusive. Piezo proteins, including Piezo1 and 2, are mechanosensing ion channels that mediate various biological phenomena. Although renal Piezo2 expression and its alteration in rodent dehydration and hypertension models have been reported, the role of Piezo1 in hypertensive nephropathy and podocyte injury is unclear. In this study, we examined Piezo1 expression and localization in the kidneys of control mice and in those of mice with hypertensive nephrosclerosis. Uninephrectomized, aldosterone-infused, salt-loaded mice developed hypertension, albuminuria, podocyte injury, and glomerulosclerosis. RNAscope in situ hybridization revealed that Piezo1 expression was enhanced in the podocytes, mesangial cells, and distal tubular cells of these mice compared to those of the uninephrectomized, vehicle-infused control group. Piezo1 upregulation in the glomeruli was accompanied by the induction of podocyte injury-related markers, plasminogen activator inhibitor-1 and serum/glucocorticoid regulated kinase 1. These changes were reversed by antihypertensive drug. Exposure of Piezo1-expressing cultured podocytes to mechanical stretch activated Rac1 and upregulated the above-mentioned markers, which was antagonized by the Piezo1 blocker grammostola mechanotoxin #4 (GsMTx4). Administration of Piezo1-specific agonist Yoda1 mimicked the effects of mechanical stretch, which was minimized by the Yoda1-specific inhibitor Dooku1 and Rac inhibitor. Rac1 was also activated in the above-mentioned hypertensive mice, and Rac inhibitor downregulated gene expression of podocyte injury-related markers in vivo. Our results suggest that Piezo1 plays a role in mechanical stress-induced podocyte injury.

Piezo Proteins and their role in Cupping Therapy (Hijama); An Interpretation of Novel Mechanism

Piezo proteins are ion channel proteins found in various cells of the human body which detect mechanical forces and convert them into electrical signals that can be interpreted by the nervous system. Recent research has shown that these proteins play an important role in a number of physiological processes, including touch sensation, hearing, proliferation, pain modulation and blood pressure regulation. Further research is ongoing to understand the importance of piezo proteins in human health and disease, that could lead to develop the newer therapies for a wide range of conditions. Some physical therapies including Cupping therapy (CT) (Hijama), a well-known regimental therapy in Greco-Arab (Unani) and Chinese medicine, is reported to treat a variety of diseases like, blood pressure and prevents cardiovascular diseases. It is also effective in treating oral and genital ulceration, musculoskeletal pain, nonspecific low back pain, neck pain, fibromyalgia, headache and migraine. Besides various theories hypothesized to explain mechanism of cupping therapy, the piezo protein gates intruded by this therapy may be the best feasible way to understand the mechanism of action of cupping. This novel hypothetical mechanism could pave the way for more researches in medical field especially in chronic ailments. 
 Key words: Cupping, Human Health, Pain, Piezo protein, Unani

Piezo Mediates the Mechanosensation and Injury-Repair of Pulpo-Dentinal Complex

ObjectivesThe aim of this research was to investigate the functions of Piezo channels in dentin defect, including mechanical signalling and odontoblast responses. MethodsRat dentin-defect models were constructed, and spatiotemporal expression of Piezo proteins was detected in the pulpo-dentinal complex. Real-time polymerase chain reaction (rtPCR) was used to investigate the functional expression pattern of Piezo channels in odontoblasts. Moreover, RNA interference technology was employed to uncover the underlying mechanisms of the Piezo-driven inflammatory response and repair under fluid shear stress (FSS) conditions in vitro. ResultsPiezo1 and Piezo2 were found to be widely expressed in the odontoblast layer and dental pulp in the rat dentin-defect model during the end stage of reparative dentin formation. The expression levels of the Piezo1 and Piezo2 genes in MDPC-23 cells were high in the initial stage under FSS loading and then decreased over time. Moreover, the expression trends of inflammatory, odontogenic, and mineralisation genes were generally contrary to those of Piezo1 and Piezo2 over time. After silencing of Piezo1/Piezo2, FSS stimulation resulted in significantly higher expression of inflammatory, odontogenesis, and mineralisation genes in MDPC-23 cells. Finally, the expression of genes involved in the integrin β1/ERK1 and Wnt5b/β-catenin signalling pathways was changed in response to RNA silencing of Piezo1 and Piezo2. ConclusionsPiezo1 and Piezo2 may be involved in regulating the expression of inflammatory and odontogenic genes in odontoblasts stimulated by FSS.

<i>PIEZO2</i> gene and its role in the development of distal arthrogryposis: A literature review

BACKGROUND:PIEZO1 and PIEZO2 are mechanosensitive ion channel proteins; in humans, they are encoded by genes with identical names. PIEZO proteins convert mechanical signals into biochemical cellular responses following transduction. Recent data highlight the importance of this family of ion channel proteins in the regulation of physiological processes; however, many mechanisms remain unknown. Modern studies have proven thatPIEZO2mutations lead to the development of various forms of distal arthrogryposis.
 AIM:To analyze publications containing information onPIEZO2gene and its role in the development of distal forms of arthrogryposis.
 MATERIALS AND METHODS:This study analyzed the results ofaliterature search in the open scientific literature databases of PubMed, Cochrane Library, and eLibrary. Consequently, 40 foreign, and domestic scientific sources were extracted from 1969 to 2022.
 RESULTS:This study showed the relationship betweenPIEZO2mutations and the development of the distal forms of arthrogryposis. The study also presented the types of distal arthrogryposis and their clinical manifestations depending on the mutation of this gene.PIEZO2mutations with decreased function cause distal arthrogryposis with impaired proprioception and taction (autosomal recessive type of inheritance).PIEZO2mutations with gain-of-function cause distal arthrogryposis of types 3 and 5 (autosomal dominant inheritance).
 CONCLUSIONS:Anintegrated approach to the diagnosis and molecular genetic study will allow us to choose the best techniques and treatment of patients with this pathology. The results are useful for doctors of various specialties.

Biomimetic Liquid Metal Mechatronic Devices

AbstractPerceiving mechanical stimuli and converting them into bioelectric signals to complete sensing information transmission and computation is a fundamental mechanism for survival and evolution of natural animals. This leads to a variety of intelligent behaviors, such as processing, learning, judgment, feedback, and so on when tackling complex and changeable environmental challenges. Until now, the realization of a bionic system to mimic the above activities has long been an important goal which is mainly based on the integration of distributed functional units, lacking the coordination between functional units and the whole systems. Herein, based on the mechano‐electronic coupling effect of liquid metals and by following the basic principle of perception and transduction of piezo proteins, a biomimetic functional liquid metal mechatronic device is proposed with the switching behavior via establishing the reversible charge gradient. Owing to flexible features of liquid metals, this all‐soft mechatronic device exhibits excellent compliance with the whole system. Based on electrochemical characteristics of liquid metals, the passive intelligent device demonstrates versatile behaviors, such as self‐energy supply, encoding, computation, sensing, information identification, communicating, and controlling functions etc. which can only possibly be achieved by living animals. This work opens a new strategy for developing intelligent mechatronic systems.

Exploration of Piezo Channels in Bread Wheat (Triticum aestivum L.)

Piezo channels belong to an important class of cell membrane-bound, Ca2+-permeable, mechanosensitive channels consisting of a pore and multiple transmembrane helices. In plants, the functional aspects of Piezo channels have been less studied than other mechanosensitive channels. However, a few studies that have been carried out indicate the involvement of Piezo channels in stress response and developmental processes. In our analysis, we identified a total of three Piezo genes in the Triticum aestivum genome. The phylogenetic analysis revealed the monocot and dicot-specific clustering of Piezo proteins. The gene and protein structure analysis indicated their conserved architecture. The promoter region of each of the three Piezo genes contained light-, growth-and development-, hormone-, and stress-responsive cis-regulatory elements. Moreover, the differential expression of Piezo genes in tissue developmental stages and under abiotic and biotic stress conditions indicated their probable role in plant growth and development and various stresses. The quantitative real-time polymerase chain reaction (qRT-PCR) analysis suggested that TaPiezo1-D might be involved in Ca2+ homeostasis. In addition, protein–protein interaction indicated their precise role in glucose, hormone and stress responses. The miRNA interaction analysis further suggested their participation in signaling cascades and biological processes. The present study will extend our understanding about Piezo channels in Ca2+ mediated signaling in plants under various stresses and provide a path for the functional validation of TaPiezo genes in future research.

Robotic Locomotion and Piezo1 Activity Controlled with Novel Liquid Marble‐based Soft Actuators

AbstractA novel soft actuator is designed, fabricated, and optimized for applied use in soft robotics and biomedical applications. The soft actuator is powered by the expansion and contraction of a graphene‐containing and encased liquid marble using the photothermal effect. Unfortunately, conventional liquid marbles are found to be too fragile and prone to cracking and failure for such applications. After experimentation, it is possible to remedy this problem by synthesizing liquid marbles encased with polymeric shells–polymerized in situ–for added mechanical strength and robustness. These marbles are shown to have intrinsic photothermal activity. They are then situated in bimorph‐type soft actuators where one side of the actuator has a dramatically different Young's modulus than the other, leading to directional actuation which is successfully demonstrated in multistep walking soft robots. The soft actuators are shown to successfully activate the mechanosensitive Piezo protein in a transfected human cell line with high effectiveness and no toxicity. Overall, the liquid marble‐powered soft actuators described here represent a new soft actuation methodology and a novel tool for mechanobiological studies, such as stem cell fate and organoid differentiation.

Optical control of PIEZO1 channels

PIEZO proteins are unusually large, mechanically-activated trimeric ion channels. The central pore features structural similarities with the pore of other trimeric ion channels, including purinergic P2X receptors, for which optical control of channel gating has been previously achieved with photoswitchable azobenzenes. Extension of these chemical optogenetics methods to mechanically-activated ion channels would provide tools for specific manipulation of pore activity alternative to non-specific mechanical stimulations. Here we report 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 transmembrane helix 38, rapidly triggers channel gating upon 365-nm-light irradiation. We provide 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. These results push the limits of azobenzene-based methods to unusually large ion channels and provide a simple stimulation means to specifically interrogate PIEZO1 function.

Force-sensing in Piezo ion channels.

In 2010, Piezo proteins were discovered, which has led to stunning progress in the elucidation of the molecular basis for mechanosensation. Piezo channels are mechanosensitive ion channels that locally curve the membrane into a dome shape. Membrane elasticity theory predicts that the curved shape of the Piezo dome deforms the surrounding lipid membrane into a membrane footprint, which may amplify Piezo's sensitivity to applied forces and explain the observed modulation of Piezo gating through the cytoskeleton. We directly test the membrane elasticity theory of Piezo's membrane footprint through cryo-electron tomography of lipid bilayer vesicles deformed by Piezo channels, finding quantitative agreement between observed and predicted membrane shapes, with no free parameters. On this basis, it becomes possible to deduce elastic properties of membrane proteins solely from membrane shape measurements. We thus derive a force-distortion relationship for the Piezo dome, from which we infer the Piezo dome's intrinsic radius of curvature and bending stiffness in free-standing lipid membranes mimicking cell membranes, and predict Piezo's gating curve, with no free parameters. Our results suggest that Piezo's intrinsic curvature, membrane footprint, small stiffness, and large area are the key properties of Piezo that give rise to low-threshold, high-sensitivity mechanical gating.

Sequence Similarity among Structural Repeats in the Piezo Family of Mechanosensitive Ion Channels

Members of the Piezo family of mechanically activated cation channels are involved in multiple physiological processes in higher eukaryotes, including vascular development, cell differentiation, touch perception, hearing, and more, but they are also common in single-celled eukaryotic microorganisms. Mutations in these proteins in humans are associated with a variety of diseases, such as colorectal adenomatous polyposis, dehydrated hereditary stomatocytosis, and hereditary xerocytosis. Available 3D structures for Piezo proteins show nine regions of four transmembrane segments each that have the same fold. Despite the remarkable similarity among the nine characteristic structural repeats in the family, no significant sequence similarity among them has been reported. Using bioinformatics approaches and the Transporter Classification Database (TCDB) as reference, we reliably identified sequence similarity among repeats based on four lines of evidence: (1) hidden Markov model-profile similarities across repeats at the family level, (2) pairwise sequence similarities between different repeats across Piezo homologs, (3) Piezo-specific conserved sequence signatures that consistently identify the same regions across repeats, and (4) conserved residues that maintain the same orientation and location in 3D space.

Piezo protein determines stem cell fate by transmitting mechanical signals.

Piezo ion channel is a mechanosensitive protein on the cell membrane, which contains Piezo1 and Piezo2. Piezo channels are activated by mechanical forces, including stretch, matrix stiffness, static pressure, and shear stress. Piezo channels transmit mechanical signals that cause different downstream responses in the differentiation process, including integrin signaling pathway, ERK1/2 MAPK signaling pathway, Notch signaling, and WNT signaling pathway. In the fate of stem cell differentiation, scientists found differences in Piezo channel expression and found that Piezo channel expression is related to developmental diseases. Here, we briefly review the structure and function of Piezo channels and the relationship between Piezo and mechanical signals, discussing the current understanding of the role of Piezo channels in stem cell fate and associated molecules and developmental diseases. Ultimately, we believe this review will help identify the association between Piezo channels and stem cell fate.

A reverse vaccinology approach identifies putative vaccination targets in the zoonotic nematode Ascaris.

Ascariasis is the most prevalent helminthic disease affecting both humans and pigs and is caused by the roundworms Ascaris lumbricoides and Ascaris suum. While preventive chemotherapy continues to be the most common control method, recent reports of anthelminthic resistance highlight the need for development of a vaccine against ascariasis. The aim of this study was to use a reverse vaccinology approach to identify potential vaccine candidates for Ascaris. Three Ascaris proteomes predicted from whole-genome sequences were analyzed. Candidate proteins were identified using open-access bioinformatic tools (e.g., Vacceed, VaxiJen, Bepipred 2.0) which test for different characteristics such as sub-cellular location, T-cell and B-cell molecular binding, antigenicity, allergenicity and phylogenetic relationship with other nematode proteins. From over 100,000 protein sequences analyzed, four transmembrane proteins were predicted to be non-allergen antigens and potential vaccine candidates. The four proteins are a Piezo protein, two voltage-dependent calcium channels and a protocadherin-like protein, are all expressed in either the muscle or ovaries of both Ascaris species, and all contained high affinity epitopes for T-cells and B-cells. The use of a reverse vaccinology approach allowed the prediction of four new potential vaccination targets against ascariasis in humans and pigs. These targets can now be further tested in in vitro and in vivo assays to prove efficacy in both pigs and humans.

Quantitative prediction and measurement of Piezo's membrane footprint

Piezo proteins are mechanosensitive ion channels that can locally curve the membrane into a dome shape [Y. R. Guo, R. MacKinnon, eLife 6, e33660 (2017)]. The curved shape of the Piezo dome is expected to deform the surrounding lipid bilayer membrane into a membrane footprint, which may serve to amplify Piezo's sensitivity to applied forces [C. A. Haselwandter, R. MacKinnon, eLife 7, e41968 (2018)]. If Piezo proteins are embedded in lipid bilayer vesicles, the membrane shape deformations induced by the Piezo dome depend on the vesicle size. We employ here membrane elasticity theory to predict, with no free parameters, the shape of such Piezo vesicles outside the Piezo dome, and show that the predicted vesicle shapes agree quantitatively with the corresponding measured vesicle shapes obtained through cryoelectron tomography, for a range of vesicle sizes [W. Helfrich, Z. Naturforsch. C 28, 693-703 (1973)]. On this basis, we explore the coupling between Piezo and membrane shape and demonstrate that the features of the Piezo dome affecting Piezo's membrane footprint approximately follow a spherical cap geometry. Our work puts into place the foundation for deducing key elastic properties of the Piezo dome from membrane shape measurements and provides a general framework for quantifying how proteins deform bilayer membranes.

Cooperative and Geometry-Dependent Mechanochromic Reactivity through Aromatic Fusion of Two Rhodamines in Polymers.

The unique topological features of Piezo proteins underlie the lever-like cellular mechanotransduction mechanism. This knowledge inspires us to seek topological/geometric control of mechanochromophores with unprecedentedly amplified, synergistic changes in polymers to serve as ideal stress probes. Here, by judicious placement of two spirolactam rings into aminobenzopyranoxanthene, a series of stereo- and regio-isomeric rhodamine-like mechanophores are developed. With two labile bonds closely coupled into one rigidified scaffold, these π-fused bis-mechanophores enable mechanochromic polymers, featuring cooperative bond scission, low rupture force (lower than rhodamine), and geometry-controlled ring-opening reactivity. Sonication, single-molecule force spectroscopy experiments, and density functional theory calculations provide insight into the force-color relationship and rationalize how the difference in reactivity of the four isomeric mechanophores is affected by their molecular geometry and thermodynamic equilibrium. Our strategy based on the aromatic fusion of bis-mechanophore promises a modular approach to isomeric mechanophores for cooperative bond scission. Also, important insights into internal and external factors governing tandem mechanochemical reactions are gained.

Computer simulations of Piezo1 channel regulation by membrane and small molecule

PIEZO proteins are homotrimeric cation-selective mechanosensitive ion channels that transduce various forms of mechanical forces into intracellular biochemical signals. Using multi-scale molecular dynamics simulations, we have generated an open state of the PIEOZ1 channel from the cryo-EM structure of a nonconducting conformation that reproduces unitary ionic conductance and selectivity in wild-type and mutants channels (Jiang, et al. Commun. Biol. 2021). This open state further allowed us to validate a putative allosteric agonist binding site of Yoda1 we previously identified using MD simulation and electrophysiology (Botello-Smith, et al.

Discovery of temperature and touch receptors: An introduction of the 2021 Nobel Prize in Physiology or Medicine

<p indent=0mm>Human has five senses, including vision, touch, hearing, taste, smell and taste, as well as temperature (including heat and cold) and pain sensation. How humans perceive the physical world through somatic sensation has fascinated us for centuries. The 2021 Nobel Prize in Physiology or Medicine was awarded to David Julius from the University of California, San Francisco (UCSF) and Ardem Patapoutian from Scripps Institute for their thermal and mechanical transducers discoveries. David Julius pursued a project to identify the receptor for capsaicin in the late 1990s. He screened a cDNA library from rodent dorsal root ganglia, identified a cDNA encoding a novel ion channel belonging to the superfamily of transient receptor potential (TRP) cation channels (now called TRPV1). In subsequent studies, TRPV1 demonstrated a pronounced activation by heat (especially above 40°C) and led to cellular calcium influx. Patch-clamp recordings revealed a heat-evoked membrane current similar to those of sensory neurons. Furthermore, high temperatures above 40°C have already been harmful to the human body. Because mice lacking Trpv1 showed only a minor loss of acute noxious heat sensation, other heat-sensitive receptors must exist. In 2011, Voets and his team identified TRPM3 as a second heat-sensitive receptor. In 2004, Julius noticed TRPA1, another superfamily of transient receptor potential (TRP) cation channels, can be activated by various chemical substances, as well as by cold and heat. In 2002, Julius and Patapoutian identified TRPM8 and found it can be activated by low temperature, which humans perceive as innocuous cold. At present, important roles for TRPV1, TRPA1, TRPM3, and TRPM8 in temperature sensing have been experimentally established. Thus, the discovery of TRPV1 by David Julius opened the door and represented a landmark achievement to a molecular understanding of thermosensation. Future studies will likely provide additional insights into this active research field. Ardem Patapoutian mainly focuses on the research of mechanosensitive ion channels. He identified a mechanosensitive Neuro2A cell line by using brief and rapid indentation of the plasma membrane in combination with patch-clamp recording. Ardem Patapoutian screened 72 candidate genes, including known ion channels and proteins of unknown function. The candidate genes were silenced by RNA interference one by one. Knockdown of the FAM38A, eliminated the mechanically activated current and the protein was named Piezo1. A second mechanosensitive channel Piezo2, was discovered by sequence homology. Piezo1 and Piezo2 represent an entirely novel class of ion channels as mechanical sensors. In 2014, Patapoutian found mice lacking Piezo2 in neither Merkel cells nor sensory neurons deficient in light touch sensation. Patapoutian also demonstrated that Piezo2 is the principal transduction channel for proprioception in mice. In further work, Patapoutian and his group found central roles of Piezo1 and Piezo2 for many physiological functions. The mutations in the <italic>Piezo2</italic> gene cause several genetic disorders manifested by altered sensations of touch, vibration and proprioception in humans. The discovery of Piezo proteins provides insights into how humans perceive internal and external environments. This review focuses on the 2021 Nobel Prize in Physiology or Medicine. Recent other research on sensory perceptions is also briefly introduced.