Search Results (112)

Terminal glial cells (TGCs) of cutaneous end-organ complexes have traditionally been regarded as structural and trophic elements, although they may also participate in mechanosensory processing. We performed an exploratory immunohistochemical and immunofluorescence study of mechanosensitivity-associated ion channel proteins in human Meissner and Pacinian corpuscles using archival formalin-fixed, paraffin-embedded glabrous skin from 64 donors and several anatomical sites. Immunoreactivity was assessed separately in mechanoreceptor axons and TGCs. In Meissner corpuscles, TGC-associated immunoreactivity for ASIC2 and TRPV4 was observed in subsets of evaluable corpuscles, whereas TRPA1 immunoreactivity was observed in selected specimens. PIEZO1- and PIEZO2-associated immunoreactivity was observed in subsets of corpuscles from the single available labia minora specimen. Among evaluable Pacinian corpuscles, inner-core TGC-associated immunoreactivity was observed for ASIC2, PIEZO2, TRPA1, and TRPV4. Because Pacinian corpuscles were unevenly distributed and scarce outside hand and foot skin, these findings were interpreted exclusively descriptively. To our knowledge, TRPA1 immunoreactivity has not previously been described in TGCs of human sensory corpuscles. These findings are hypothesis-generating and do not demonstrate protein function or mechanotransduction. Because this study used archival tissue and independent target validation was not performed, the results require confirmation using orthogonal antibody- or transcript-based approaches. Full article

Background: Impaired insulin secretion by pancreatic beta cells drives chronic hyperglycemia, which characterizes type 2 diabetes mellitus. The mechanosensitive ion channel Piezo2 has been implicated in various physiological processes. However, its expression and functional role in pancreatic endocrine cells remain poorly understood. Methods: We investigated the expression, cellular localization, and potential functional significance of Piezo2 in the pancreatic islets of mice fed normal- and high-fat diets (HFD) using molecular, immunohistochemical, and immunofluorescence approaches. Results: Piezo2 mRNA and protein expression were detected in rat pancreatic tissue and the pancreatic beta cell line INS-1 via polymerase chain reaction and Western blotting analyses. Hematoxylin and eosin staining and histopathological analysis were performed to determine the localization of Piezo2, insulin, and glucagon in the islets of Langerhans from mouse pancreas. Immunofluorescence revealed that Piezo2 colocalized with insulin, glucagon, pancreatic polypeptide (PP, a pancreatic cell marker), and insulin/PP (suggesting Ppy-lineage beta cells). Piezo2 expression is significantly reduced in islets from HFD-fed mice and downregulated under high glucose conditions in INS-1 cells. Stretch stimulation, with or without D-GsMTx4 (a Piezo2-specific inhibitor), enhanced glucose-stimulated insulin secretion, whereas ruthenium red (a non-specific Piezo channel inhibitor) did not alter the response to high glucose. Conclusions: These findings demonstrate Piezo2 expression in pancreatic islets and suggest that it is enriched in beta cells and Ppy-lineage beta cells, minority in alpha cells and is responsive to metabolic stress. Although Piezo2 may contribute to beta-cell adaptation, its role in insulin secretion remains unclear. Full article

Piezo1 mechanosensitive ion channels convert mechanical stimuli into biochemical signals across diverse tissues, yet their role in the contractile function of adult skeletal muscle remains unclear. Here, we demonstrate that Piezo1 regulates skeletal muscle mechanics through a channel-independent mechanism that tunes the length-tension relationship. We examined the effects of pharmacological modulation using the Piezo1 agonist Yoda1 and antagonist Dooku1 in individual muscle fibers from wild-type mice and from muscles with reduced Piezo1 expression (anti-Piezo1 shRNA) using calcium influx and electrophysiological assays. Ex vivo force measurements were performed on these muscles and compared with the dystrophic mdx model. Piezo1 activation had no effect on force at resting length, whereas its inhibition significantly reduced contractile force at stretched lengths, indicating a selective role in length-dependent force regulation. This effect was independent of extracellular calcium and diminished by Piezo1 knockdown. This reduction was absent in mdx muscle, demonstrating dependence on an intact dystrophin-associated cytoskeleton. These findings identify Piezo1 as a previously unrecognized regulator of muscle mechanical performance that operates independently of ion conduction. Our results uncover a mechanobiological interface between Piezo1 and cytoskeletal integrity, expanding current concepts of muscle mechanoregulation and highlighting Piezo1 as a potential therapeutic target for improving muscle function. Full article

Ion channels are validated drug targets, but they remain difficult to study as their pharmacology is influenced by rapid gating, conformational state transitions, cell-type-specific expression, and narrow safety margins. Recent advances in cryo-electron microscopy, structure-based in silico screening, machine-learning-guided prioritization, optical high-throughput screening, automated patch-clamp electrophysiology, and human-relevant organoid or microphysiological system (MPS) models are transforming this field. In this expanded review, we examine how these modalities can be integrated into a hybrid discovery pipeline that begins with computational triage, proceeds through scalable functional screening and state-aware electrophysiological validation, and concludes with multi-channel safety de-risking and translational analysis in complex human models. We also discuss disease-associated channel remodeling in cancer and inflammatory disorders, with an emphasis on transient receptor potential channels, voltage-gated potassium channel 1.3 (Kv1.3), Piezo channels, transmembrane protein 16A/anoctamin-1 (TMEM16A/ANO1), chloride channels, and proarrhythmic safety risks. Additionally, we highlight unresolved challenges, including bias in artificial intelligence models, incomplete conformational sampling, assay interference, organoid heterogeneity, and regulatory acceptance of MPS platforms. This review proposes a staged decision framework in which computational prioritization, scalable functional screening, direct electrophysiological confirmation, safety pharmacology, DMPK assessment, and disease-relevant human models serve as complementary filters rather than competing platforms for the identification of selective and translatable ion-channel therapeutics. Full article

Background: Complex Regional Pain Syndrome type 1 (CRPS-1) is a multifactorial disorder characterized by persistent pain, neuroinflammation, and tissue remodeling following trauma in the absence of overt nerve injury. Despite advances in understanding its pathophysiology, the mechanisms underlying the transition to chronic pain remain incompletely defined, and reliable circulating biomarkers are lacking. Piezo-type mechanosensitive ion channel component 1 (Piezo 1), a mechanosensitive ion channel that transduces mechanical stimuli into intracellular calcium signaling, has emerged as a regulator of inflammation, extracellular matrix remodeling, and cellular stress responses. Experimental evidence indicates that Piezo 1 activation can modulate cytokine production and mechanotransduction pathways relevant to chronic pain and inflammatory conditions. Methods: In this study, we evaluated circulating Piezo 1 levels in CRPS-1 patients and explored their association with clinical parameters and response to neridronate treatment. Results: Although Piezo 1 levels were significantly altered compared to controls, no associations were observed with pain intensity or therapeutic response. Conclusions: These findings suggest that, despite its biological relevance, circulating Piezo 1 is not a clinically informative biomarker in CRPS-1. The results support a predominantly local role of Piezo 1-mediated mechanotransduction in processes relevant to chronic inflammation and nociceptive sensitization. Full article

The human liver is a polyploid organ, dominantly featured by a high proportion of binuclear polyploid hepatocytes. Our recent study demonstrates that decline of the abundance of binuclear hepatocytes (ABH) plays a critical role in contributing to Hepatocellular carcinoma (HCC) formation, involving the cytokinesis regulator Anillin. However, the relevance between liver stiffness and the acquired ABH attenuation remains unclear. In this study, we set a mechanical environment gel with different gradients to simulate different liver stiffness environments, combined with the paired paracancerous liver tissues from real-world patients with HCC who underwent radical surgery. A mechanosensitive Piezo1/RUNX2/Anillin axis was discovered. As observed, the decline of ABH in paracancerous liver tissues is a noteworthy measurable value for tumor formation, correlated with the extent of liver matrix stiffness and dismal phenotypes. A stiffened culture environment may promote quick polyploid attenuation of hepatocytes, accompanied by high expression of Piezo1, a critical mechanosensitive ion channel, and a consequential nuclear translocation of RUNX2. Importantly, RUNX2 functions as an upstream transcription factor of Anillin. Regulating Piezo1/RUNX2 or using Piezo1 agonist remarkably affected Anillin expression and hepatocyte polyploidy homeostasis. Thus, we propose that the Piezo1/RUNX2/Anillin axis transduces the microenvironment mechanical signal from liver stiffening and impairs hepatocyte polyploidy homeostasis in HCC formation. Full article

Big Bang theories are connected to gravity by force of attraction. Forced lengthening, like eccentric contractions, instigate proprioception as a result of working against gravity. Piezo2, as the principal mechanosensory ion channel responsible for proprioception, is theorized to fine-modulate these anti-gravitational contractions in order to provide system-wide ultrafast postural control. This mechanism may instantaneously emit energy and force through Piezo2 in order to offset gravity by anti-gravity entropic-spring-like stochastic mechanics and it is suggested to be propagated by quantum tunneling of protons (and electrons). However, a Piezo2-initiated wormhole-like mechanism with the contribution of cryptochromes should be considered as part of this ultrafast long-distance non-synaptic neurotransmission, although the quantum gravity concept is short of being unequivocally proven to be unified with quantum theory. The impairment of this theoretical ultrafast signaling is analogous to a Big Bang-like mechanism within a given compartment, or acquired Piezo2 channelopathy, leading to the principal gateway to pathophysiology. Full article

Intracranial atherosclerosis (ICAS) is a distinct, inflammation-dominant vasculopathy and a leading cause of global stroke morbidity. Unlike extracranial atherosclerosis (ECAS), which often utilizes compensatory positive remodeling to maintain patency, ICAS is characterized by a unique architecture and a localized antioxidant gap that favor maladaptive negative remodeling. We critically analyze the molecular cascade initiated by the breakdown of the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) and the Krüppel-like factor 2/4 (KLF2/4) mechanotransduction axis, which triggers endothelial nitric oxide synthase (eNOS) uncoupling and establishes a state of chronic inflammation. This environment facilitates the subendothelial lipid retention of oxidized low-density lipoprotein (oxLDL), a process exacerbated by the intracranial deficiency of Apolipoprotein A-I (ApoA-I) and impaired glymphatic clearance. Crucially, we evaluate how these metabolic and mechanical insults drive vascular smooth muscle cell (VSMC) phenotypic switching; the transdifferentiation of contractile VSMCs into macrophage-like foam cells accounts for up to 60% of the plaque’s lipid-laden pool and destabilizes the fibrous cap. This vascular failure directly compromises the neurovascular unit (NVU), leading to pericyte dropout and blood–brain barrier breakdown. Beyond environmental stressors, we highlight the ring finger protein 213 (RNF213) variant as a critical genetic determinant of this susceptibility. Shifting the clinical paradigm from simple luminal narrowing toward the identification of the vulnerable plaque, we discuss how High-Resolution Vessel Wall Imaging (HR-VWI) and microRNA biomarkers can identify unstable lesions. By integrating these molecular and imaging signatures, we propose a precision medicine framework centered on the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the NVU to effectively mitigate the high residual recurrence risk that persists under conventional therapy. Full article

Mechanosensitive ion channels (MSCs) are fundamental transducers that convert mechanical forces into electrochemical signals, enabling cells to regulate processes such as Ca²⁺ homeostasis, migration, proliferation, and adhesion. Located in both plasma and organellar membranes, MSCs, including Piezos, TRPs, K2Ps, MscL, and MscS families exhibit diverse ion selectivity, gating mechanisms and physiological roles. Emerging evidence demonstrates that lipids are dynamic regulators of MSC activation, sensitivity, and kinetics. Endogenous membrane lipids such as cholesterol, phospholipids, sphingolipids and fatty acids modulate MSC behavior by altering bilayer tension, curvature, stiffness and protein–lipid interactions. Exogenous lipids, including dietary fatty acids and lipid-derived metabolites, influence MSCs by modifying membrane physical properties or engaging specific lipid-binding sites on channel proteins. These interactions shape fundamental biological processes and contribute to disease mechanisms in cardiovascular dysfunction, neurological disorders, metabolic disease, and cancer. Despite significant progress, the molecular principles by which lipids regulate MSC conformational transitions and force sensing remain incompletely defined. This review synthesizes current knowledge on endogenous and exogenous lipid modulation of MSCs, integrating structural, computational and electrophysiological insights to highlight emerging therapeutic opportunities targeting lipid–mechanotransduction interfaces. Full article

PIEZO1 are Ca²⁺-permeable mechanogated channels that play a crucial role in numerous fundamental cellular responses. Ca²⁺ influx via PIEZO1 could control the activity of various Ca²⁺-dependent molecules within the cells, thus activating Ca²⁺-dependent signaling processes and reactions. Previously, we demonstrated Ca²⁺-mediated coupling between PIEZO1 and KCa channels in the plasma membranes of transformed mouse fibroblasts, where a Ca²⁺ influx through PIEZO1 stimulates the activity of functionally co-localized KCa channels. Importantly, the selective PIEZO1 activator Yoda1 inhibited transformed fibroblast migration, induced F-actin assembly, and stress fiber formation. However, the impact of PIEZO1-KCa channel coupling on the observed effects remains unknown. Here, we performed the molecular identification of KCa channels in transformed mouse fibroblasts. Importantly, TRAM-34, a specific KCa3.1 channel blocker, abrogated the effect of Yoda1 on F-actin organization and fibroblast motility. We conclude that KCa3.1 channels in the plasma membrane are primary downstream effectors and critical contributors to the decrease in transformed fibroblast migration and F-actin assembly caused by selective PIEZO1 activation. Full article

As cancer mortality rates rise globally, malignancies have become the second leading cause of death. Recently, efforts have been made to understand the impact of the tumor microenvironment that involves fluid shear forces. Biomechanical stimulation, which uses shear stress to activate mechanosensitive ion channels, e.g., Piezo1, increases calcium influx into the intracellular space and activates T cells. Novel 3D cancer cultures with T cells have been proposed. Such models use cell/scaffold constructs to recapitulate interactions between cells and the extracellular matrix. In addition, flow perfusion bioreactors investigate the impact of fluid shear forces on immune and/or cancer cells. These bioreactors have biosensors that allow monitoring of immune cell activation. Furthermore, they provide a biomimetic environment for the study of the interaction of T cells and cancer cells. Hence, immune checkpoint inhibitors have demonstrated immunotherapeutic efficacy, but a single-target blockade has often proved insufficient. Co-delivery of CCL19 pDNA and the PD-1/PD-L1 interaction inhibitor BMS-1 using RGD-modified nanocarriers targeting tumor integrins enhanced local antitumor immunity. This review highlights recent insights into how fluid shear stress (FSS) regulates cancer progression and immune responses in three-dimensional in vitro models, with a focus on bioreactors and the surface modification of scaffold materials. Full article

Most transient receptor potential (TRP) channels are Ca²⁺-permeable non-selective cation channels that function as polymodal receptors activated by a wide variety of stimuli, including natural compounds such as pungent substances, physical stimuli, lipids, intracellular signaling molecules, and ions. Their physiological roles are diverse, including sensory perception, ion transport, and intracellular signaling. Similarly, Piezo channels, which are also Ca²⁺-permeable non-selective cation channels, are activated by mechanical stimuli such as membrane stretching and contribute to touch sensation, blood flow regulation, and bladder-filling sensation, among other functions. While research on non-selective cation channels in relation to energy metabolism has primarily focused on TRP channels expressed in primary afferent neurons, studies over the past decade have revealed the important roles of TRP and Piezo channels in brown adipocytes. In this review, we highlight evidence regarding the contributions of TRPV2 and Piezo1 to brown adipocyte differentiation and thermogenesis and briefly summarize recent advances regarding other TRP channels expressed in brown adipocytes. Furthermore, we propose a conceptual framework in which a “modal shift” in TRP/Piezo channels, defined as developmental stage-dependent changes in their functional properties, may contribute to the regulation of brown adipocytes’ functions. Full article

Infrasound, physically defined as sound at frequencies below 20 Hertz, can travel long distances with minimal attenuation and permeate biological tissues due to its marked particle displacement and deep penetration. Generated by both natural phenomena and human-made systems, infrasound has drawn increasing scientific and public attention regarding its potential physiological and psychological effects. Experimental studies demonstrate that infrasound can modulate mechanosensitive structures at the cellular level, particularly pressure-sensitive ion channels such as PIEZO1 and TRPV4, leading to intracellular calcium influx, oxidative stress, altered intercellular communication, and in some settings, apoptosis. These responses vary according to sound pressure levels, frequencies, exposure duration, and tissue type. In the cardiovascular system, higher sound pressures have been associated with mitochondrial injury and fibrosis, whereas low sound pressures may exert context-dependent protective effects. In animal models, prolonged or intense exposure to infrasound has been shown to induce neuroinflammatory responses and memory impairment. Short-term studies in humans at moderate intensities have reported minimal physiological changes, with psychological and contextual factors influencing symptom perception. Occupational environments such as factories and agricultural settings may contain elevated levels of infrasound, underscoring the importance of systematic measurements and exposure assessments. At the same time, controlled infrasound stimulation has shown potential as an adjunct modality in bone repair and tissue regeneration, highlighting its dual capacity as both a biological stressor and a possible therapeutic tool. Overall, existing data indicate that infrasound may be harmful at chronic exposure depending on intensity and frequency, yet beneficial when precisely regulated. Future research should standardize exposure metrics, refine measurement technologies, and clarify dose–response relationships to better define the health risks and therapeutic applications of infrasound. Full article

Exposure to microgravity results in cardiovascular deconditioning, with endothelial cell apoptosis recognized as a pivotal initiating event. However, the mechanosensitive mechanisms underlying this process remain poorly understood. Here, we demonstrate that the expression of mechanosensitive ion channel protein PIEZO1 is upregulated in human umbilical vein endothelial cells (HUVECs) under simulated microgravity. Functional studies revealed that PIEZO1 activation promotes endothelial apoptosis under simulated microgravity conditions. Proteomic analysis following PIEZO1 knockdown revealed extensive alterations in biological processes associated with apoptosis. Furthermore, we found that PIEZO1 activation triggers calcium influx, leading to elevated expression of the HMGA2. Moreover, we identify that PIEZO1 activation induces calcium influx, which subsequently elevates the expression of HMGA2. The knockdown of HMGA2 significantly mitigated microgravity-induced endothelial apoptosis, indicating its role in PIEZO1-mediated apoptosis. These findings reveal a novel PIEZO1–Ca²⁺–HMGA2 axis critical for microgravity-induced endothelial apoptosis, providing mechanistic insight into cardiovascular adaptation to spaceflight and potential therapeutic targets for countermeasure development. Full article

Endothelial ion signaling is crucial for the proper function of the arterial microcirculation, regulating local blood flow to meet metabolic demands and contributing to the regulation of systemic arterial pressure. The role of endothelial ion channels in the precise control of vascular resistance has been primarily investigated in animal models, where the microvasculature is more readily accessible. This review aims to discuss current knowledge on the role of endothelial ion signaling in vasomotor regulation in the human microcirculation, focusing on potassium (K⁺) channels (K_IR2.1, K_ATP, SK_Ca/IK_Ca), Transient Receptor Potential (TRP) channels, particularly TRP Vanilloid 1 (TRPV1) and TRPV4, and Piezo1 channels. The analysis examines the organization of the endothelial ionic signaling machinery in the most extensively studied human microvascular beds, such as the skin, skeletal muscle, and brain, while also discussing vascular reactivity in vessels isolated ex vivo. Accumulating evidence indicates that a distinct repertoire of endothelial ion channels engages diverse endothelium-dependent vasorelaxant pathways across different vascular beds. Understanding how endothelial channels regulate the microvascular unit is predicted to foster the search for alternative therapeutic strategies for treating cardiovascular and neurodegenerative disorders associated with endothelial dysfunction. Full article