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Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1.

ABSTRACT: Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca²⁺) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd³⁺). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A₂ (PLA₂), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA.

SUBMITTER: Lawrence KM

PROVIDER: S-EPMC5505992 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.

Project description:Cells can respond to mechanical stress by gating mechanosensitive ion channels (MSCs). The cloning of Piezo1, a eukaryotic cation selective MSC, defines a new system for studying mechanical transduction at the cellular level. Because Piezo1 has electrophysiological properties similar to those of endogenous cationic MSCs that are selectively inhibited by the peptide GsMTx4, we tested whether the peptide targets Piezo1 activity. Extracellular GsMTx4 at micromolar concentrations reversibly inhibited ∼80% of the mechanically induced current of outside-out patches from transfected HEK293 cells. The inhibition was voltage insensitive, and as seen with endogenous MSCs, the mirror image d enantiomer inhibited like the l. The rate constants for binding and unbinding based on Piezo1 current kinetics provided association and dissociation rates of 7.0 × 10(5) M(-1) s(-1) and 0.11 s(-1), respectively, and a K(D) of ∼155 nM, similar to values previously reported for endogenous MSCs. Consistent with predicted gating modifier behavior, GsMTx4 produced an ∼30 mmHg rightward shift in the pressure-gating curve and was active on closed channels. In contrast, streptomycin, a nonspecific inhibitor of cationic MSCs, showed the use-dependent inhibition characteristic of open channel block. The peptide did not block currents of the mechanical channel TREK-1 on outside-out patches. Whole-cell Piezo1 currents were also reversibly inhibited by GsMTx4, and although the off rate was nearly identical to that of outside-out patches, differences were observed for the on rate. The ability of GsMTx4 to target the mechanosensitivity of Piezo1 supports the use of this channel in high-throughput screens for pharmacological agents and diagnostic assays.

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Immunoregulatory Role of the Mechanosensitive Ion Channel Piezo1 in Inflammation and Cancer.

Project description:Piezo1 was originally identified as a mechanically activated, nonselective cation ion channel, with significant permeability to calcium ions, is evolutionally conserved, and is involved in the proliferation and development of various types of cells, in the context of various types of mechanical or innate stimuli. Recently, our study and work by others have reported that Piezo1 from all kinds of immune cells is involved in regulating many diseases, including infectious inflammation and cancer. This review summarizes the recent progress made in understanding the immunoregulatory role and mechanisms of the mechanical receptor Piezo1 in inflammation and cancer and provides new insight into the biological significance of Piezo1 in regulating immunity and tumors.

| S-EPMC9822220 | biostudies-literature

The mechanosensitive ion channel PIEZO1 promotes satellite cell function in muscle regeneration.

Project description:Muscle satellite cells (MuSCs), myogenic stem cells in skeletal muscles, play an essential role in muscle regeneration. After skeletal muscle injury, quiescent MuSCs are activated to enter the cell cycle and proliferate, thereby initiating regeneration; however, the mechanisms that ensure successful MuSC division, including chromosome segregation, remain unclear. Here, we show that PIEZO1, a calcium ion (Ca2+)-permeable cation channel activated by membrane tension, mediates spontaneous Ca2+ influx to control the regenerative function of MuSCs. Our genetic engineering approach in mice revealed that PIEZO1 is functionally expressed in MuSCs and that Piezo1 deletion in these cells delays myofibre regeneration after injury. These results are, at least in part, due to a mitotic defect in MuSCs. Mechanistically, this phenotype is caused by impaired PIEZO1-Rho signalling during myogenesis. Thus, we provide the first concrete evidence that PIEZO1, a bona fide mechanosensitive ion channel, promotes proliferation and regenerative functions of MuSCs through precise control of cell division.

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Mechanosensitive Ion Channel Piezo1 Regulates Diet-Induced Adipose Inflammation and Systemic Insulin Resistance.

Project description:Adipocytes function as an energy buffer and undergo significant size and volume changes in response to nutritional cues. This adipocyte plasticity is important for systemic lipid metabolism and insulin sensitivity. Accompanying the adipocyte size and volume changes, the mechanical pressure against cell membrane also changes. However, the role that mechanical pressure plays in lipid metabolism and insulin sensitivity remains to be elucidated. Here we show that Piezo1, a mechanically-activated cation channel stimulated by membrane tension and stretch, was highly expressed in adipocytes. Adipose Piezo1 expression was increased in obese mice. Adipose-specific piezo1 knockout mice (adipose-Piezo1-/-) developed insulin resistance, especially when challenged with a high-fat diet (HFD). Perigonadal white adipose tissue (pgWAT) weight was reduced while pro-inflammatory and lipolysis genes were increased in the pgWAT of HFD-fed adipose-Piezo1-/- mice. The adipose-Piezo1-/- mice also developed hepatic steatosis with elevated expression of fatty acid synthesis genes. In cultured adipocytes, Piezo1 activation decreased, while Piezo1 inhibition elevated pro-inflammatory gene expression. TLR4 antagonist TAK-242 abolished adipocyte inflammation induced by Piezo1 inhibition. Thus, adipose Piezo1 may serve as an adaptive mechanism for adipocyte plasticity restraining pro-inflammatory response in obesity.

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Mechanosensitive ion channel Piezo1 is expressed in antral G cells of murine stomach.

Project description:G cells in the antrum region of the murine stomach produce gastrin, the central hormone for controlling gastric activities. Secretion of gastrin is induced mainly by protein breakdown products but also by distensions of the stomach wall. Although G cells respond to protein fragments via distinct chemosensory receptor types, the mechanism underlying G cell activation upon distention is entirely ambiguous. Mechanosensitive ion channels are considered as potential candidates for such a task. Therefore, we explore the possibility of whether Piezo1, a polymodal sensor for diverse mechanical forces, is expressed in antral G cells. The experimental analyses revealed that the vast majority of G cells indeed expressed Piezo1. Within flask-like G cells at the base of the antral invaginations, the Piezo1 protein was primarily located at the basolateral portion, which is thought to be the release site for the exocytic secretion of gastrin. In the spindle-like G cells, which are oriented parallel to the invaginations, Piezo1 protein was restricted to the cell body where the hormone was also located, whereas the long processes appeared to be devoid of Piezo1 protein. Our results suggest that mechanosensitive channels such as Piezo1, located in close proximity to hormone-release sites, enable G cells to respond directly to antrum distensions with gastrin secretion.

| S-EPMC5784007 | biostudies-literature

The Mechanosensitive Ion Channel Piezo1 Significantly Mediates In Vitro Ultrasonic Stimulation of Neurons.

Project description:Ultrasound brain stimulation is a promising modality for probing brain function and treating brain disease non-invasively and with high spatiotemporal resolution. However, the mechanism underlying its effects remains unclear. Here, we examine the role that the mouse piezo-type mechanosensitive ion channel component 1 (Piezo1) plays in mediating the in vitro effects of ultrasound in mouse primary cortical neurons and a neuronal cell line. We show that ultrasound alone could activate heterologous and endogenous Piezo1, initiating calcium influx and increased nuclear c-Fos expression in primary neurons but not when pre-treated with a Piezo1 inhibitor. We also found that ultrasound significantly increased the expression of the important proteins phospho-CaMKII, phospho-CREB, and c-Fos in a neuronal cell line, but Piezo1 knockdown significantly reduced this effect. Our findings demonstrate that the activity of mechanosensitive ion channels such as Piezo1 stimulated by ultrasound is an important contributor to its ability to stimulate cells in vitro.

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The mechanosensitive ion channel Piezo1 modulates the migration and immune response of microglia.

Project description:Microglia are the brain's resident immune cells, performing surveillance to promote homeostasis and healthy functioning. While microglial chemical signaling is well-studied, mechanical cues regulating their function are less well-understood. Here, we investigate the role of the mechanosensitive ion channel Piezo1 in microglia migration, pro-inflammatory cytokine production, and stiffness sensing. In Piezo1 knockout transgenic mice, we demonstrated the functional expression of Piezo1 in microglia and identified genes whose expression was consequently affected. Functional assays revealed that Piezo1 deficiency in microglia enhanced migration toward amyloid β-protein, and decreased levels of pro-inflammatory cytokines produced upon stimulation by lipopolysaccharide, both in vitro and in vivo. The phenomenon could be mimicked or reversed chemically using a Piezo1-specific agonist or antagonist. Finally, we also showed that Piezo1 mediated the effect of substrate stiffness-induced migration and cytokine expression. Altogether, we show that Piezo1 is an important molecular mediator for microglia, its activation modulating microglial migration and immune responses.

| S-EPMC9926228 | biostudies-literature

Mechanosensitive Ion Channel PIEZO1 Signaling in the Hall-Marks of Cancer: Structure and Functions.

Project description:Tumor cells alter their characteristics and behaviors during tumorigenesis. These characteristics, known as hallmarks of cancer, are crucial for supporting their rapid growth, need for energy, and adaptation to tumor microenvironment. Tumorigenesis is also accompanied by alteration in mechanical properties. Cells in tumor tissue sense mechanical signals from the tumor microenvironment, which consequently drive the acquisition of hallmarks of cancer, including sustained proliferative signaling, evading growth suppressors, apoptosis resistance, sustained angiogenesis, metastasis, and immune evasion. Piezo-type mechanosensitive ion channel component 1 (Piezo1) is a mechanically sensitive ion channel protein that can be activated mechanically and is closely related to various diseases. Recent studies showed that Piezo1 mediates tumor development through multiple mechanisms, and its overexpression is associated with poor prognosis. Therefore, the discovery of Piezo1, which links-up physical factors with biological properties, provides a new insight for elucidating the mechanism of tumor progression under a mechanical microenvironment, and suggests its potential application as a tumor marker and therapeutic target. In this review, we summarize current knowledge regarding the role of Piezo1 in regulating cancer hallmarks and the underlying molecular mechanisms. Furthermore, we discuss the potential of Piezo1 as an antitumor therapeutic target and the limitations that need to be overcome.

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The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction.

Project description:The beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank-Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive. Here we show that the mechanically activated Piezo1 channel converts mechanical stretch of cardiomyocytes into Ca2+ and reactive oxygen species (ROS) signaling, which critically determines the mechanical activity of the heart. Either cardiac-specific knockout or overexpression of Piezo1 in mice results in defective Ca2+ and ROS signaling and the development of cardiomyopathy, demonstrating a homeostatic role of Piezo1. Piezo1 is pathologically upregulated in both mouse and human diseased hearts via an autonomic response of cardiomyocytes. Thus, Piezo1 serves as a key cardiac mechanotransducer for initiating mechano-chemo transduction and consequently maintaining normal heart function, and might represent a novel therapeutic target for treating human heart diseases.

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The mechanosensitive Piezo1 channel is required for bone formation.

Project description:Mechanical load of the skeleton system is essential for the development, growth, and maintenance of bone. However, the molecular mechanism by which mechanical stimuli are converted into osteogenesis and bone formation remains unclear. Here we report that Piezo1, a bona fide mechanotransducer that is critical for various biological processes, plays a critical role in bone formation. Knockout of Piezo1 in osteoblast lineage cells disrupts the osteogenesis of osteoblasts and severely impairs bone structure and strength. Bone loss that is induced by mechanical unloading is blunted in knockout mice. Intriguingly, simulated microgravity treatment reduced the function of osteoblasts by suppressing the expression of Piezo1. Furthermore, osteoporosis patients show reduced expression of Piezo1, which is closely correlated with osteoblast dysfunction. These data collectively suggest that Piezo1 functions as a key mechanotransducer for conferring mechanosensitivity to osteoblasts and determining mechanical-load-dependent bone formation, and represents a novel therapeutic target for treating osteoporosis or mechanical unloading-induced severe bone loss.

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