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Severe skin wounds arising from burns, cancers, and accidents can damage the entire tissue structure, resulting in permanent somatosensory dysfunction in patients. Although emerging hydrogel dressings have shown clinical potential for accelerating wound repair, the use of an individual material to synchronously restore the tissue structure and sensory function of defective skin remains a challenge. Herein, a multifunctional hydrogel that combines electroconductive polydopamine‐capped graphene nanosheets (PrGOs) embedded in a dynamically crosslinked dual‐polysaccharide (xyloglucan and chitosan) matrix network is presented. The fabricated hydrogels have an adjustable modulus that can be matched to skin tissue at the wound site, owing to the dynamic Schiff‐based crosslinking as well as the facile photo‐triggered secondary crosslinking. Furthermore, the photothermal activity of PrGO can elevate the local temperature up to ≈50 °C, significantly restraining bacterial growth. These two factors jointly promote the regeneration of skin tissue. Tissue adhesion of hydrogels is also reported that offers a conformable and robust interface that can detect and quantify human movement and physiological signals to mimic the human skin somatosensory system. This hydrogel offers an effective one‐stone‐for‐two‐birds material that simultaneously achieves tissue regeneration and multi‐signal sensing, promoting the restoration and/or replacement of the structure and function of damaged skins. [ABSTRACT FROM AUTHOR]

The propeller-shaped blades of the PIEZO1 and PIEZO2 ion channels partition into the plasma membrane and respond to indentation or stretching of the lipid bilayer, thus converting mechanical forces into signals that can be interpreted by cells, in the form of calcium flux and changes in membrane potential. While PIEZO channels participate in diverse physiological processes, from sensing the shear stress of blood flow in the vasculature to detecting touch through mechanoreceptors in the skin, the molecular details that enable these mechanosensors to tune their responses over a vast dynamic range of forces remain largely uncharacterized. To survey the molecular landscape surrounding PIEZO channels at the cell surface, we employed a mass spectrometry-based proteomic approach to capture and identify extracellularly exposed proteins in the vicinity of PIEZO1. This PIEZO1-proximal interactome was enriched in surface proteins localized to cell junctions and signaling hubs within the plasma membrane. Functional screening of these interaction candidates by calcium imaging and electrophysiology in an overexpression system identified the adhesion molecule CADM1/SynCAM that slows the inactivation kinetics of PIEZO1 with little effect on PIEZO2. Conversely, we found that CADM1 knockdown accelerates inactivation of endogenous PIEZO1 in Neuro-2a cells. Systematic deletion of CADM1 domains indicates that the transmembrane region is critical for the observed effects on PIEZO1, suggesting that modulation of inactivation is mediated by interactions in or near the lipid bilayer. [ABSTRACT FROM AUTHOR]

The lining of blood vessels is constantly exposed to mechanical forces exerted by blood flow against the endothelium. Endothelial cells detect these tangential forces (i.e., shear stress), initiating a host of intracellular signaling cascades that regulate vascular physiology. Thus, vascular health is tethered to the endothelial cells' capacity to transduce shear stress. Indeed, the mechanotransduction of shear stress underlies a variety of cardiovascular benefits, including some of those associated with increased physical activity. However, endothelial mechanotransduction is impaired in aging and disease states such as obesity and type 2 diabetes, precipitating the development of vascular disease. Understanding endothelial mechanotransduction of shear stress, and the molecular and cellular mechanisms by which this process becomes defective, is critical for the identification and development of novel therapeutic targets against cardiovascular disease. In this review, we detail the primary mechanosensitive structures that have been implicated in detecting shear stress, including junctional proteins such as platelet endothelial cell adhesion molecule-1 (PECAM-1), the extracellular glycocalyx and its components, and ion channels such as piezo1. We delineate which molecules are truly mechanosensitive and which may simply be indispensable for the downstream transmission of force. Furthermore, we discuss how these mechanosensors interact with other cellular structures, such as the cytoskeleton and membrane lipid rafts, which are implicated in translating shear forces to biochemical signals. Based on findings to date, we also seek to integrate these cellular and molecular mechanisms with a view of deciphering endothelial mechanotransduction of shear stress, a tenet of vascular physiology. [ABSTRACT FROM AUTHOR]

Many organs are designed to move: the heart pumps each second, the gastrointestinal tract squeezes and churns to digest food, and we contract and relax skeletal muscles to move our bodies. Sensory neurons of the peripheral nervous system detect signals from bodily tissues, including the forces generated by these movements, to control physiology. The processing of these internal signals is called interoception, but this is a broad term that includes a wide variety of both chemical and mechanical sensory processes. Mechanical senses are understudied, but rapid progress has been made in the last decade, thanks in part to the discovery of the mechanosensory PIEZO ion channels (Coste et al., 2010). The role of these mechanosensors within the interoceptive nervous system is the focus of this review. In defining the transduction molecules that govern mechanical interoception, we will have a better grasp of how these signals drive physiology. [ABSTRACT FROM AUTHOR]

Fluid shear stress (FSS) from blood flow, sensed by the vascular endothelial cells (ECs) that line all blood vessels, regulates vascular development during embryogenesis, controls adult vascular physiology and determines the location of atherosclerotic plaque formation. Although a number of papers have reported a crucial role for cell-cell adhesions or adhesion receptors in these processes, a recent publication has challenged this paradigm, presenting evidence that ECs can very rapidly align in fluid flow as single cells without cell–cell contacts. To address this controversy, four independent laboratories assessed EC alignment in fluid flow across a range of EC cell types. These studies demonstrate a strict requirement for cell-cell contact in shear stress sensing over timescales consistent with previous literature and inconsistent with the newly published data. [ABSTRACT FROM AUTHOR]

Gut motility undergoes a switch from myogenic to neurogenic control in late embryonic development. Here, we report on the electrical events that underlie this transition in the enteric nervous system, using the GCaMP6f reporter in neural crest cell derivatives. We found that spontaneous calcium activity is tetrodotoxin (TTX) resistant at stage E11.5, but not at E18.5. Motility at E18.5 was characterized by periodic, alternating high‐ and low‐frequency contractions of the circular smooth muscle; this frequency modulation was inhibited by TTX. Calcium imaging at the neurogenic‐motility stages E18.5–P3 showed that CaV1.2‐positive neurons exhibited spontaneous calcium activity, which was inhibited by nicardipine and 2‐aminoethoxydiphenyl borate (2‐APB). Our protocol locally prevented muscle tone relaxation, arguing for a direct effect of nicardipine on enteric neurons, rather than indirectly by its relaxing effect on muscle. We demonstrated that the ENS was mechanosensitive from early stages on (E14.5) and that this behaviour was TTX and 2‐APB resistant. We extended our results on L‐type channel‐dependent spontaneous activity and TTX‐resistant mechanosensitivity to the adult colon. Our results shed light on the critical transition from myogenic to neurogenic motility in the developing gut, as well as on the intriguing pathways mediating electro‐mechanical sensitivity in the enteric nervous system. Highlights: What is the central question of this study?What are the first neural electric events underlying the transition from myogenic to neurogenic motility in the developing gut, what channels do they depend on, and does the enteric nervous system already exhibit mechanosensitivity?What is the main finding and its importance?ENS calcium activity is sensitive to tetrodotoxin at stage E18.5 but not E11.5. Spontaneous electric activity at fetal and adult stages is crucially dependent on L‐type calcium channels and IP3R receptors, and the enteric nervous system exhibits a tetrodotoxin‐resistant mechanosensitive response. Abstract figure legend Tetrodotoxin‐resistant Ca2+ rise induced by mechanical stimulation in the E18.5 mouse duodenum. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract is an organ actively involved in mechanical processes, where it detects forces via a mechanosensation mechanism. Mechanosensation relies on specialized cells termed mechanoreceptors, which convert mechanical forces into electrochemical signals via mechanosensors. The mechanosensitive Piezo1 and Piezo2 are widely expressed in various mechanosensitive cells that respond to GI mechanical forces by altering transmembrane ionic currents, such as epithelial cells, enterochromaffin cells, and intrinsic and extrinsic enteric neurons. This review highlights recent research advances on mechanosensitive Piezo channels in GI physiology and pathology. Specifically, the latest insights on the role of Piezo channels in the intestinal barrier, GI motility, and intestinal mechanosensation are summarized. Additionally, an overview of Piezo channels in the pathogenesis of GI disorders, including irritable bowel syndrome, inflammatory bowel disease, and GI cancers, is provided. Overall, the presence of mechanosensitive Piezo channels offers a promising new perspective for the treatment of various GI disorders. [ABSTRACT FROM AUTHOR]

As the early step of food ingestion, the swallow is under rigorous sensorimotor control. Nevertheless, the mechanisms underlying swallow control at a molecular and circuitry level remain largely unknown. Here, we find that mutation of the mechanotransduction channel genes nompC, Tmc, or piezo impairs the regular pumping rhythm of the cibarium during feeding of the fruit fly Drosophila melanogaster. A group of multi-dendritic mechanosensory neurons, which co-express the three channels, wrap the cibarium and are crucial for coordinating the filling and emptying of the cibarium. Inhibition of them causes difficulty in food emptying in the cibarium, while their activation leads to difficulty in cibarium filling. Synaptic and functional connections are detected between the pharyngeal mechanosensory neurons and the motor circuit that controls swallow. This study elucidates the role of mechanosensation in swallow, and provides insights for a better understanding of the neural basis of food swallow.

Background: Human respiratory sensory gating is a neural process associated with inhibiting the cortical processing of repetitive respiratory mechanical stimuli. While this gating is typically examined in the time domain, the neural oscillatory dynamics, which could offer supplementary insights into respiratory sensory gating, remain unknown. The purpose of the present study was to investigate central neural gating of respiratory sensation using both time- and frequency-domain analyses. Methods: A total of 37 healthy adults participated in this study. Two transient inspiratory occlusions were presented within one inspiration, while responses in the electroencephalogram (EEG) were recorded. N1 amplitudes and oscillatory activities to the first stimulus (S1) and the second stimulus (S2) were measured. The perceived level of breathlessness and level of unpleasantness elicited by the occlusions were measured after the experiment. Results: As expected, the N1 peak amplitude to the S1 was significantly larger than to the S2. The averaged respiratory sensory gating S2/S1 ratio for the N1 peak amplitude was 0.71. For both the evoked- and induced-oscillations, time-frequency analysis showed higher theta activations in response to S1 relative to S2. A positive correlation was observed between the perceived unpleasantness and induced theta power. Conclusions: Our results suggest that theta oscillations, evoked as well as induced, reflect the “gating” of respiratory sensation. Theta oscillation, particularly theta-induced power, may be indicative of the emotional processing of respiratory mechanosensation. The findings of this study serve as a foundation for future investigations into the underlying mechanisms of respiratory sensory gating, particularly in patient populations.

Mechanosensory neurons that innervate the tongue provide essential information to guide feeding, speech, and social grooming. We use in vivo calcium imaging of mouse trigeminal ganglion neurons to identify functional groups of mechanosensory neurons innervating the anterior tongue. These sensory neurons respond to thermal and mechanical stimulation. Analysis of neuronal activity patterns reveal that most mechanosensory trigeminal neurons are tuned to detect moving stimuli across the tongue. Using an unbiased, multilayer hierarchical clustering approach to classify pressure-evoked activity based on temporal response dynamics, we identify five functional classes of mechanosensory neurons with distinct force-response relations and adaptation profiles. These populations are tuned to detect different features of touch. Molecular markers of functionally distinct clusters are identified by analyzing cluster representation in genetically marked neuronal subsets. Collectively, these studies provide a platform for defining the contributions of functionally distinct mechanosensory neurons to oral behaviors crucial for survival in mammals.

Endothelial cells (ECs) line the inner surface of all blood vessels and form a barrier that facilitates the controlled transfer of nutrients and oxygen from the circulatory system to surrounding tissues. Exposed to both laminar and turbulent blood flow, ECs are continuously subject to differential mechanical stimulation. It has been well established that the shear stress associated with laminar flow (LF) is atheroprotective, while shear stress in areas with turbulent flow (TF) correlates with EC dysfunction. Moreover, ECs show metabolic adaptions to physiological changes, such as metabolic shifts from quiescence to a proliferative state during angiogenesis. The AMP-activated protein kinase (AMPK) is at the center of these phenomena. AMPK has a central role as a metabolic sensor in several cell types. Moreover, in ECs, AMPK is mechanosensitive, linking mechanosensation with metabolic adaptions. Finally, recent studies indicate that AMPK dysregulation is at the center of cardiovascular disease (CVD) and that pharmacological targeting of AMPK is a promising and novel strategy to treat CVDs such as atherosclerosis or ischemic injury. In this review, we summarize the current knowledge relevant to this topic, with a focus on shear stress-induced AMPK modulation and its consequences for vascular health and disease. [ABSTRACT FROM AUTHOR]

The skin is the largest organ in the human body and serves various functions, including mechanical protection and mechanosensation. Yet, even though skin's biomechanics are attributed to two main layers—epidermis and dermis—computational models have often treated this tissue as a thin homogeneous material or, when considering multiple layers, have ignored the most prominent heterogeneities of skin seen at the mesoscale. Here, we create finite element models of representative volume elements (RVEs) of skin, including the three-dimensional variation of the interface between the epidermis and dermis as well as considering the presence of hair follicles. The sinusoidal interface, which approximates the anatomical features known as Rete ridges, does not affect the homogenized mechanical response of the RVE but contributes to stress concentration, particularly at the valleys of the Rete ridges. The stress profile is three-dimensional due to the skin's anisotropy, leading to high-stress bands connecting the valleys of the Rete ridges through one type of saddle point. The peaks of the Rete ridges and the other class of saddle points of the sinusoidal surface form a second set of low-stress bands under equi-biaxial loading. Another prominent feature of the heterogeneous stress pattern is a switch in the stress jump across the interface, which becomes lower with respect to the flat interface at increasing deformations. These features are seen in both tension and shear loading. The RVE with the hair follicle showed strains concentrating at the epidermis adjacent to the hair follicle, the epithelial tissue surrounding the hair right below the epidermis, and the bulb or base region of the hair follicle. The regions of strain concentration near the hair follicle in equi-biaxial and shear loading align with the presence of distinct mechanoreceptors in the skin, except for the bulb or base region. This study highlights the importance of skin heterogeneities, particularly its potential mechanophysiological role in the sense of touch and the prevention of skin delamination. [ABSTRACT FROM AUTHOR]

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Proprioception provides important sensory feedback regarding the position of an animal’s body and limbs in space. This interacts with a central pattern generator responsible for rhythmic movement, to adapt locomotion to the demands that an animal’s environment places on it. The mechanisms by which this feedback is enabled are poorly understood, which belies its importance: dysfunctional proprioception is associated with movement disorder and improving it can help reduce the severity of symptoms. Similarly, proprioception is important for guiding accurate robotic movement and for understanding how sensory systems capture and process information to guide action selection. It is therefore important to interpret research that investigates mechanisms of proprioception, to ask: what type of information do proprioceptive sensors capture, and how do they capture it? Work in mammalian models has made important progress towards answering this question. So too, has research conducted Drosophila. Fruit fly proprioceptors are more accessible than mammalian equivalents and can be manipulated using a unique genetic toolkit, so experiments conducted in the invertebrate can make a significant contribution to overall understanding. It can be difficult, however, to relate work conducted in different models, to draw general conclusions about proprioception. This review, therefore, explores what research in the fruit fly has revealed about proprioceptor function, to highlight its potential translation to mammals. Specifically, the present text presents evidence that differential expression of mechanoelectrical transducers contributes to tuning of fly proprioceptors and suggests that the same mechanism may play a role in tuning mammalian proprioceptors.

Abstract A metabotropic glutamate receptor coupled to phospholipase D (PLD‐mGluR) was discovered in the hippocampus over three decades ago. Its pharmacology and direct linkage to PLD activation are well established and indicate it is a highly atypical glutamate receptor. A receptor with the same pharmacology is present in spindle primary sensory terminals where its blockade can totally abolish, and its activation can double, the normal stretch‐evoked firing. We report here the first identification of this PLD‐mGluR protein, by capitalizing on its expression in primary mechanosensory terminals, developing an enriched source, pharmacological profiling to identify an optimal ligand, and then functionalizing it as a molecular tool. Evidence from immunofluorescence, western and far‐western blotting indicates PLD‐mGluR is homomeric GluK2, since GluK2 is the only glutamate receptor protein/receptor subunit present in spindle mechanosensory terminals. Its expression was also found in the lanceolate palisade ending of hair follicle, also known to contain the PLD‐mGluR. Finally, in a mouse model with ionotropic function ablated in the GluK2 subunit, spindle glutamatergic responses were still present, confirming it acts purely metabotropically. We conclude the PLD‐mGluR is a homomeric GluK2 kainate receptor signalling purely metabotropically and it is common to other, perhaps all, primary mechanosensory endings.

The sense of touch is crucial for cognitive, emotional, and social development and relies on mechanically activated (MA) ion channels that transduce force into an electrical signal. Despite advances in the molecular characterization of these channels, the physiological factors that control their activity are poorly understood. Here, we used behavioral assays, electrophysiological recordings, and various mouse strains (males and females analyzed separately) to investigate the role of the calmodulin-like Ca2+ sensor, caldendrin, as a key regulator of MA channels and their roles in touch sensation. In mice lacking caldendrin (Cabp1 KO), heightened responses to tactile stimuli correlate with enlarged MA currents with lower mechanical thresholds in dorsal root ganglion neurons (DRGNs). The expression pattern of caldendrin in the DRG parallels that of the major MA channel required for touch sensation, PIEZO2. In transfected cells, caldendrin interacts with and inhibits the activity of PIEZO2 in a manner that requires an alternatively spliced sequence in the N-terminal domain of caldendrin. Moreover, targeted genetic deletion of caldendrin in Piezo2-expressing DRGNs phenocopies the tactile hypersensitivity of complete Cabp1 KO mice. We conclude that caldendrin is an endogenous repressor of PIEZO2 channels and their contributions to touch sensation in DRGNs. [ABSTRACT FROM AUTHOR]

Currently, TREK-1 is considered to be the main mechanosensitive channel in detrusor smooth muscle (DSM) cells. The aim of our study was to detect the functioning of the K+-conducting mechanosensitive TREK-1 channel in rat DSM cells using the patch-clamp technique in response to hydrodynamic stimulation (shear stress) and to determine the effects of a TREK-1 agonist – arachidonic acid (AA) and an antagonist – L-methionine. Mechanical stimulation of DSM cells using hydrodynamic stress led to the appearance of a membrane current with signs of pronounced outward rectification at positive membrane potentials, which is typical of TREK-1 activation. The application of AA (50 mcmol/l) activated a current with similar characteristics of the outward rectification to the shear stress-activated one. L-methionine (10 mcmol/l) almost completely prevented the generation of an outwardly rectifying current in response to shear stress stimulation. DSM cells also retained the ability to generate a mechanoactivated current with a more pronounced inward component when extracellular and intracellular K+ were replaced by Cs+. It was concluded that the dominant mechanoactivated current in rat DSM cells is carried by K+-selective TREK-1 channels, but a small portion of this current can also be carried by other nonselective mechanosensitive cation channels [ABSTRACT FROM AUTHOR]

The intestine is the largest mechanosensitive organ in the human body whose epithelial cells, smooth muscle cells, neurons and enteroendocrine cells must sense and respond to various mechanical stimuli such as motility, distension, stretch and shear to regulate physiological processes including digestion, absorption, secretion, motility and immunity. Piezo channels are a newly discovered class of mechanosensitive ion channels consisting of two subtypes, Piezo1 and Piezo2. Piezo channels are widely expressed in the intestine and are involved in physiological and pathological processes. The present review summarizes the current research progress on the expression, function and regulation of Piezo channels in the intestine, with the aim of providing a reference for the future development of therapeutic strategies targeting Piezo channels. [ABSTRACT FROM AUTHOR]

Simple Summary: One major challenge when using animal models to study cognition is that we cannot ask them what they are thinking or how they are feeling; instead, we measure the animal's behavior. For honeybees, the extension of the proboscis (their tongue-like structure) occurs when they are presented with a sucrose solution, and they can be trained to associate a neutral cue—for example, an odor—with the occurrence of this food reward, eventually extending the proboscis when presented with the neutral cue rather than the food cue. Thus, the proboscis extension response (PER) is useful for exploring honeybees' sensory perception, learning, and memory. In this study, we tested a new stimulus, namely different speeds of air flow, to investigate whether honeybees were able to associate this cue with the reward. Additionally, we designed a new system for performing PER experiments wherein the stimulus delivery and analyses are entirely automated, rather than performed manually. Using this enhanced method, we found that honeybees succeeded when a lower air flux was rewarded, but not when a higher air flux was rewarded. These results add to our knowledge of stimulus intensity encoding, while our improved PER system will offer technical advantages for such experiments in the future. The proboscis extension response (PER) has been widely used to evaluate honeybees' (Apis mellifera) learning and memory abilities, typically by using odors and visual cues for the conditioned stimuli. Here we asked whether honeybees could learn to distinguish between different magnitudes of the same type of stimulus, given as two speeds of air flux. By taking advantage of a novel automated system for administering PER experiments, we determined that the bees were highly successful when the lower air flux was rewarded and less successful when the higher flux was rewarded. Importantly, since our method includes AI-assisted analysis, we were able to consider subthreshold responses at a high temporal resolution; this analysis revealed patterns of rapid generalization and slowly acquired discrimination between the rewarded and unrewarded stimuli, as well as indications that the high air flux may have been mildly aversive. The learning curve for these mechanosensory stimuli, at least when the lower flux is rewarded, more closely mimics prior data from olfactory PER studies rather than visual ones, possibly in agreement with recent findings that the insect olfactory system is also sensitive to mechanosensory information. This work demonstrates a new modality to be used in PER experiments and lays the foundation for deeper exploration of honeybee cognitive processes when posed with complex learning challenges. [ABSTRACT FROM AUTHOR]

A metabotropic glutamate receptor coupled to phospholipase D (PLD‐mGluR) was discovered in the hippocampus over three decades ago. Its pharmacology and direct linkage to PLD activation are well established and indicate it is a highly atypical glutamate receptor. A receptor with the same pharmacology is present in spindle primary sensory terminals where its blockade can totally abolish, and its activation can double, the normal stretch‐evoked firing. We report here the first identification of this PLD‐mGluR protein, by capitalizing on its expression in primary mechanosensory terminals, developing an enriched source, pharmacological profiling to identify an optimal ligand, and then functionalizing it as a molecular tool. Evidence from immunofluorescence, western and far‐western blotting indicates PLD‐mGluR is homomeric GluK2, since GluK2 is the only glutamate receptor protein/receptor subunit present in spindle mechanosensory terminals. Its expression was also found in the lanceolate palisade ending of hair follicle, also known to contain the PLD‐mGluR. Finally, in a mouse model with ionotropic function ablated in the GluK2 subunit, spindle glutamatergic responses were still present, confirming it acts purely metabotropically. We conclude the PLD‐mGluR is a homomeric GluK2 kainate receptor signalling purely metabotropically and it is common to other, perhaps all, primary mechanosensory endings. What is the central question of this study?The metabotropic glutamate receptor coupled to phospholipase D (PLD‐mGluR) is a glutamate receptor previously only characterized pharmacologically but essential for maintaining stretch responsiveness in muscle spindle mechanosensory primary endings: what is the PLD‐mGluR protein?What is the main finding and its importance?PLD‐mGluR was identified as a homomeric GluK2 receptor signalling metabotropically. This identifies PLD‐mGluR 30 years after its discovery. This is important because: PLD‐mGluR is essential for muscle spindle stretch sensitivity; it is the first native kainate receptor shown to signal solely metabotropically; and, as it is the only GluR expressed in spindle mechanosensory endings, muscle spindles make a good functional assay of the native receptor. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract is an organ actively involved in mechanical processes, where it detects forces via a mechanosensation mechanism. Mechanosensation relies on specialized cells termed mechanoreceptors, which convert mechanical forces into electrochemical signals via mechanosensors. The mechanosensitive Piezo1 and Piezo2 are widely expressed in various mechanosensitive cells that respond to GI mechanical forces by altering transmembrane ionic currents, such as epithelial cells, enterochromaffin cells, and intrinsic and extrinsic enteric neurons. This review highlights recent research advances on mechanosensitive Piezo channels in GI physiology and pathology. Specifically, the latest insights on the role of Piezo channels in the intestinal barrier, GI motility, and intestinal mechanosensation are summarized. Additionally, an overview of Piezo channels in the pathogenesis of GI disorders, including irritable bowel syndrome, inflammatory bowel disease, and GI cancers, is provided. Overall, the presence of mechanosensitive Piezo channels offers a promising new perspective for the treatment of various GI disorders.

A complete map of the external sense organs shows how fruit fly larvae detect different aspects of their environment.

Rapid conversion of force into a biological signal enables living cells to respond to mechanical forces in their environment. The force is believed to initially affect the plasma membrane and then alter the behavior of membrane proteins. Phospholipase D2 (PLD2) is a mechanosensitive enzyme that is regulated by a structured membrane-lipid site comprised of cholesterol and saturated ganglioside (GM1). Here we show stretch activation of TWIK-related K+ channel (TREK-1) is mechanically evoked by PLD2 and spatial patterning involving ordered GM1 and 4,5-bisphosphate (PIP2) clusters in mammalian cells. First, mechanical force deforms the ordered lipids, which disrupts the interaction of PLD2 with the GM1 lipids and allows a complex of TREK-1 and PLD2 to associate with PIP2 clusters. The association with PIP2 activates the enzyme, which produces the second messenger phosphatidic acid (PA) that gates the channel. Co-expression of catalytically inactive PLD2 inhibits TREK-1 stretch currents in a biological membrane. Cellular uptake of cholesterol inhibits TREK-1 currents in culture and depletion of cholesterol from astrocytes releases TREK-1 from GM1 lipids in mouse brain. Depletion of the PLD2 ortholog in flies results in hypersensitivity to mechanical force. We conclude PLD2 mechanosensitivity combines with TREK-1 ion permeability to elicit a mechanically evoked response.

Myocardial damage caused, for example, by cardiac ischemia leads to ventricular volume overload resulting in increased stretch of the remaining myocardium. In adult mammals, these changes trigger an adaptive cardiomyocyte hypertrophic response which, if the damage is extensive, will ultimately lead to pathological hypertrophy and heart failure. Conversely, in response to extensive myocardial damage, cardiomyocytes in the adult zebrafish heart and neonatal mice proliferate and completely regenerate the damaged myocardium. We therefore hypothesized that in adult zebrafish, changes in mechanical loading due to myocardial damage may act as a trigger to induce cardiac regeneration. Based on this notion we sought to identify mechanosensors which could be involved in detecting changes in mechanical loading and triggering regeneration. Here we show using a combination of knockout animals, RNAseq and in vitro assays that the mechanosensitive ion channel Trpc6a is required by cardiomyocytes for successful cardiac regeneration in adult zebrafish. Furthermore, using a cyclic cell stretch assay, we have determined that Trpc6a induces the expression of components of the AP1 transcription complex in response to mechanical stretch. Our data highlights how changes in mechanical forces due to myocardial damage can be detected by mechanosensors which in turn can trigger cardiac regeneration.

Plastin-3 (PLS3) is a calcium-sensitive actin-bundling protein that has recently been linked to the development of childhood-onset osteoporosis. Clinical data suggest that PLS3 mutations lead to a defect in osteoblast function, however the underlying mechanism remains elusive. To investigate the role of PLS3 in bone mineralization, we generated MC3T3-E1 preosteoblast cells that are stably depleted of PLS3. Analysis of osteogenic differentiation of control and PLS3 knockdown (PLS3 KD) cells showed that depletion of PLS3 does not alter the first stage of osteoblast mineralization in which a collagen matrix is deposited, but severely affects the subsequent mineralization of that matrix. During this phase, osteoblasts heavily rely on mechanosensitive signaling pathways to sustain mineral deposition in response to increasing stiffness of the extracellular matrix (ECM). PLS3 prominently localizes to focal adhesions (FAs), which are intricately linked to mechanosensation. In line with this, we observed that depletion of PLS3 rendered osteoblasts unresponsive to changes in ECM stiffness and showed the same cell size, FA lengths and number of FAs when plated on soft (6 kPa) versus stiff (100 kPa) substrates in contrast to control cells, which showed an increased in each of these parameters when plated on 100 kPa substrates. Defective cell spreading of PLS3 KD cells on stiff substrates could be rescued by expression of wildtype PLS3, but not by expression of three PLS3 mutations that were identified in patients with early onset osteoporosis and that have aberrant actin-bundling activity. Altogether, our results show that actin-bundling by PLS3 is part of the mechanosensitive mechanism that promotes osteoblast mineralization and thus begins to elucidate how PLS3 contributes to the development of bone defects such as osteoporosis. [ABSTRACT FROM AUTHOR]

Mechanosensitive channels (MS channels) are membrane proteins capable of responding to mechanical stress over a wide dynamic range of external mechanical stimuli. In recent years, it has been found that MS channels play an important role as "sentinels" in the process of cell sensing and response to extracellular and intracellular force signals. There is growing appreciation for mechanical activation of ion channels and their subsequent initiation of downstream signaling pathways. Members of the transient receptor potential (TRP) superfamily and Piezo channels are broadly expressed in human tissues and contribute to multiple cellular functions. Both TRP and Piezo channels are thought to play key roles in physiological homeostasis and pathophysiology of disease states including in the lung. Here, we review the current state of knowledge on the expression, regulation, and function of TRP and Piezo channels in the context of the adult lung across the age spectrum, and in lung diseases such as asthma, COPD and pulmonary fibrosis where mechanical forces likely play varied roles in the structural and functional changes characteristic of these diseases. Understanding of TRP and Piezo in the lung can provide insights into new targets for treatment of pulmonary disease. [ABSTRACT FROM AUTHOR]

Piezo1 and Piezo2 are mechanoreceptors involved in sensing both internal and external mechanical forces converting them in electrical signals to the brain. Piezo1 is mainly expressed in the endothelial system and in epidermis sensing shear stress and light touch. The internal traction forces generated by Myosin Light Chain Kinase (MYLK) activate Piezo1, regulating cell contraction. We observed Oenothera biennis cell culture hydro-soluble extract (ObHEx) activated MYLK regulating cell contraction ability. The aim of this work was to test the hypothesis that ObHEx activates Piezo1 through MYLK pathway using CHO cell overexpressing Piezo1, HUVEC and SHSY5Y cells endogenously expressing high levels of Piezo1. Results showed that ObHEx extracts were able to activate Piezo1 and the effect is due to Liriodendrin and Salvadoraside, the two most abundant lignans produced by the cell culture. The effect is lost in presence of MYLK specific inhibitors confirming the key role of this pathway and providing indication about the mechanism of action in Piezo1 activation by lignans. In summary, these results confirmed the connection between Piezo1 and MYLK, opening the possibility of using lignans-containing natural extracts to activate Piezo1. • We describe Oenothera biennis as the first natural extract activating Piezo1 channel. • Activation of Piezo1 is mediated by two lignans, liriodendrin and salvadoraside. • Lignans act with a Yoda-like mechanism, as their effect is abolished by Dooku1. • Piezo1 activation is also revoked in the presence of a MYLK inhibitor, ML-7. • Confirmed association between Piezo1 and MYLK signalling mechanism. [ABSTRACT FROM AUTHOR]

In living organisms, changes in calcium flux are integral to many different cellular functions and are especially critical for the activity of neurons and myocytes. Genetically encoded calcium indicators (GECIs) have been popular tools for reporting changes in calcium levels in vivo. In particular, GCaMPs, derived from GFP, are the most widely used GECIs and have become an invaluable toolkit for neurophysiological studies. Recently, new variants of GCaMP, which offer a greater variety of temporal dynamics and improved brightness, have been developed. However, these variants are not readily available to the Caenorhabditis elegans research community. This work reports a set of GCaMP6 and jGCaMP7 reporters optimized for C. elegans studies. Our toolkit provides reporters with improved dynamic range, varied kinetics, and targeted subcellular localizations. Besides optimized routine uses, this set of reporters is also well suited for studies requiring fast imaging speeds and low magnification or low-cost platforms. [ABSTRACT FROM AUTHOR]

Plant roots adapt to the mechanical constraints of the soil to grow and absorb water and nutrients. As in animal species, mechanosensitive ion channels in plants are proposed to transduce external mechanical forces into biological signals. However, the identity of these plant root ion channels remains unknown. Here, we show that Arabidopsis thaliana PIEZO1 (PZO1) has preserved the function of its animal relatives and acts as an ion channel. We present evidence that plant PIEZO1 is expressed in the columella and lateral root cap cells of the root tip, which are known to experience robust mechanical strain during root growth. Deleting PZO1 from the whole plant significantly reduced the ability of its roots to penetrate denser barriers compared to wild-type plants. pzo1 mutant root tips exhibited diminished calcium transients in response to mechanical stimulation, supporting a role of PZO1 in root mechanotransduction. Finally, a chimeric PZO1 channel that includes the C-terminal half of PZO1 containing the putative pore region was functional and mechanosensitive when expressed in naive mammalian cells. Collectively, our data suggest that Arabidopsis PIEZO1 plays an important role in root mechanotransduction and establish PIEZOs as physiologically relevant mechanosensitive ion channels across animal and plant kingdoms.

Ultrasound modulates the electrical activity of excitable cells and offers advantages over other neuromodulatory techniques; for example, it can be noninvasively transmitted through the skull and focused to deep brain regions. However, the fundamental cellular, molecular, and mechanistic bases of ultrasonic neuromodulation are largely unknown. Here, we demonstrate ultrasound activation of the mechanosensitive K+ channel TRAAK with submillisecond kinetics to an extent comparable to canonical mechanical activation. Single-channel recordings reveal a common basis for ultrasonic and mechanical activation with stimulus-graded destabilization of long-duration closures and promotion of full conductance openings. Ultrasonic energy is transduced to TRAAK through the membrane in the absence of other cellular components, likely increasing membrane tension to promote channel opening. We further demonstrate ultrasonic modulation of neuronally expressed TRAAK. These results suggest mechanosensitive channels underlie physiological responses to ultrasound and could serve as sonogenetic actuators for acoustic neuromodulation of genetically targeted cells.

ABSTRACTTMEM120A (TACAN) is an enigmatic protein with several seemingly unconnected functions. It was proposed to be an ion channel involved in sensing mechanical stimuli, and knockdown/knockout experiments have implicated that TMEM120A may be necessary for sensing mechanical pain. TMEM120A’s ion channel function has subsequently been challenged, as attempts to replicate electrophysiological experiments have largely been unsuccessful. Several cryo-EM structures revealed TMEM120A is structurally homologous to a lipid modifying enzyme called Elongation of Very Long Chain Fatty Acids 7 (ELOVL7). Although TMEM120A’s channel function is debated, it still seems to affect mechanosensation by inhibiting PIEZO2 channels and by modifying tactile pain responses in animal models. TMEM120A was also shown to inhibit polycystin-2 (PKD2) channels through direct physical interaction. Additionally, TMEM120A has been implicated in adipocyte regulation and in innate immune response against Zika virus. The way TMEM120A is proposed to alter each of these processes ranges from regulating gene expression, acting as a lipid modifying enzyme, and controlling subcellular localization of other proteins through direct binding. Here, we examine TMEM120A’s structure and proposed functions in diverse physiological contexts.

Plastin-3 (PLS3) is a calcium-sensitive actin-bundling protein that has recently been linked to the development of childhood-onset osteoporosis. Clinical data suggest that PLS3 mutations lead to a defect in osteoblast function, however the underlying mechanism remains elusive. To investigate the role of PLS3 in bone mineralization, we generated MC3T3-E1 preosteoblast cells that are stably depleted of PLS3. Analysis of osteogenic differentiation of control and PLS3 knockdown (PLS3 KD) cells showed that depletion of PLS3 does not alter the first stage of osteoblast mineralization in which a collagen matrix is deposited, but severely affects the subsequent mineralization of that matrix. During this phase, osteoblasts heavily rely on mechanosensitive signaling pathways to sustain mineral deposition in response to increasing stiffness of the extracellular matrix (ECM). PLS3 prominently localizes to focal adhesions (FAs), which are intricately linked to mechanosensation. In line with this, we observed that depletion of PLS3 rendered osteoblasts unresponsive to changes in ECM stiffness and showed the same cell size, FA lengths and number of FAs when plated on soft (6 kPa) versus stiff (100 kPa) substrates in contrast to control cells, which showed an increased in each of these parameters when plated on 100 kPa substrates. Defective cell spreading of PLS3 KD cells on stiff substrates could be rescued by expression of wildtype PLS3, but not by expression of three PLS3 mutations that were identified in patients with early onset osteoporosis and that have aberrant actin-bundling activity. Altogether, our results show that actin-bundling by PLS3 is part of the mechanosensitive mechanism that promotes osteoblast mineralization and thus begins to elucidate how PLS3 contributes to the development of bone defects such as osteoporosis.

Cells sense and respond to mechanical stimuli by converting those stimuli into biological signals, a process known as mechanotransduction. Mechanotransduction is essential in diverse cellular functions, including tissue development, touch sensitivity, pain, and neuronal pathfinding. In the search for key players of mechanotransduction, several families of ion channels were identified as being mechanosensitive and were demonstrated to be activated directly by mechanical forces in both the membrane bilayer and the cytoskeleton. More recently, Piezo ion channels were discovered as a bona fide mechanosensitive ion channel, and its characterization led to a cascade of research that revealed the diverse functions of Piezo proteins and, in particular, their involvement in neuronal repair. [ABSTRACT FROM AUTHOR]

In addition to their well-described functions in cell excitability, voltage-sensitive calcium channels (VSCCs) serve a critical role in calcium (Ca2+)-mediated secretion of pleiotropic paracrine and endocrine factors, including those produced in bone. Influx of Ca2+ through VSCCs activates intracellular signaling pathways to modulate a variety of cellular processes that include cell proliferation, differentiation, and bone adaptation in response to mechanical stimuli. Less well understood is the role of VSCCs in the control of bone and calcium homeostasis mediated through secreted factors. In this review, we discuss the various functions of VSCCs in skeletal cells as regulators of Ca2+ dynamics and detail how these channels might control the release of bioactive factors from bone cells. Because VSCCs are druggable, a better understanding of the multiple functions of these channels in the skeleton offers the opportunity for developing new therapies to enhance and maintain bone and to improve systemic health. [ABSTRACT FROM AUTHOR]

Animal feeding is controlled by external sensory cues and internal metabolic states. Does it also depend on enteric neurons that sense mechanical cues to signal fullness of the digestive tract? Here, we identify a group of piezo-expressing neurons innervating the Drosophila crop (the fly equivalent of the stomach) that monitor crop volume to avoid food overconsumption. These neurons reside in the pars intercerebralis (PI), a neuro-secretory center in the brain involved in homeostatic control, and express insulin-like peptides with well-established roles in regulating food intake and metabolism. Piezo knockdown in these neurons of wild-type flies phenocopies the food overconsumption phenotype of piezo-null mutant flies. Conversely, expression of either fly Piezo or mammalian Piezo1 in these neurons of piezo-null mutants suppresses the overconsumption phenotype. Importantly, Piezo+ neurons at the PI are activated directly by crop distension, thus conveying a rapid satiety signal along the "brain-gut axis" to control feeding.

Animals integrate information from different sensory modalities, body parts, and time points to inform behavioral choice, but the relevant sensory comparisons and the underlying neural circuits are still largely unknown. We use the grooming behavior of Drosophila melanogaster as a model to investigate the sensory comparisons that govern a motor sequence. Flies perform grooming movements spontaneously, but when covered with dust, they clean their bodies following an anterior-to-posterior sequence. After investigating different sensory modalities that could detect dust, we focus on mechanosensory bristle neurons, whose optogenetic activation induces a similar sequence. Computational modeling predicts that higher sensory input strength to the head will cause anterior grooming to occur first. We test this prediction using an optogenetic competition assay whereby two targeted light beams independently activate mechanosensory bristle neurons on different body parts. We find that the initial choice of grooming movement is determined by the ratio of sensory inputs to different body parts. In dust-covered flies, sensory inputs change as a result of successful cleaning movements. Simulations from our model suggest that this change results in sequence progression. One possibility is that flies perform frequent comparisons between anterior and posterior sensory inputs, and the changing ratios drive different behavior choices. Alternatively, flies may track the temporal change in sensory input to a given body part to measure cleaning effectiveness. The first hypothesis is supported by our optogenetic competition experiments: iterative spatial comparisons of sensory inputs between body parts is essential for organizing grooming movements in sequence.

Ion channels gated selectively by mechanical stimulus are the key elements of mechanosensation. Several genes have been associated with putative mechanosensitive ion channels or mechanosensitive channel complexes. Transmembrane channel (TMC)-like protein is one of those candidate proteins that have been explored in mammals and several invertebrates. The presence and possible function of TMC related genes has not been investigated yet in crustaceans. In the present work an mRNA coding TMC-like protein was firstly cloned in Astacus leptodactylus (Eschscholtz, 1823) (Decapoda: Astacidea: Astacidae) and expressed in HEK293T cells. Three-dimensional structural calculations of the protein predicted a channel. Functional studies, however, indicated that the mechanosensitivity of the transfected HEK293T cells is similar to that in the control cells. It was concluded that a TMC-like protein is present in the crayfish but future studies are necessary to define its function. [ABSTRACT FROM AUTHOR]

The actin cytoskeleton orchestrates cell mechanics and facilitates the physical integration of cells into tissues, while tissue‐scale forces and extracellular rigidity in turn govern cell behaviour. Here, we discuss recent evidence that actin filaments (F‐actin), the core building blocks of the actin cytoskeleton, also serve as molecular force sensors. We delineate two classes of proteins, which interpret forces applied to F‐actin through enhanced binding interactions: 'mechanically tuned' canonical actin‐binding proteins, whose constitutive F‐actin affinity is increased by force, and 'mechanically switched' proteins, which bind F‐actin only in the presence of force. We speculate mechanically tuned and mechanically switched actin‐binding proteins are biophysically suitable for coordinating cytoskeletal force‐feedback and mechanical signalling processes, respectively. Finally, we discuss potential mechanisms mediating force‐activated actin binding, which likely occurs both through the structural remodelling of F‐actin itself and geometric rearrangements of higher‐order actin networks. Understanding the interplay of these mechanisms will enable the dissection of force‐activated actin binding's specific biological functions. [ABSTRACT FROM AUTHOR]

The lateral line system of zebrafish consists of the anterior lateral line, with neuromasts distributed on the head, and the posterior lateral line, with neuromasts distributed on the trunk. The sensory afferent neurons are contained in the anterior and posterior lateral line ganglia, respectively. So far, the vast majority of physiological and developmental studies have focused on the posterior lateral line. However, studies that focus on the anterior lateral line, especially on its physiology, are very rare. The anterior lateral line involves different neuromast patterning processes, specific distribution of synapses, and a unique role in behavior. Here, we report our observations regarding the development of the lateral line and analyze the physiological responses of the anterior lateral line to mechanical and water jet stimuli. Sensing in the fish head may be crucial to avoid obstacles, catch prey, and orient in water current, especially in the absence of visual cues. Alongside the lateral line, the trigeminal system, with its fine nerve endings innervating the skin, could contribute to perceiving mechanosensory stimulation. Therefore, we compare the physiological responses of the lateral line afferent neurons to responses of trigeminal neurons and responsiveness of auditory neurons. We show that anterior lateral line neurons are tuned to the velocity of mechanosensory ramp stimulation, while trigeminal neurons either only respond to mechanical step stimuli or fast ramp and step stimuli. Auditory neurons did not respond to mechanical or water jet stimuli. These results may prove to be essential in designing underwater robots and artificial lateral lines, with respect to the spectra of stimuli that the different mechanosensory systems in the larval head are tuned to, and underline the importance and functionality of the anterior lateral line system in the larval fish head.

The proboscis extension response (PER) has been widely used to evaluate honeybees’ (Apis mellifera) learning and memory abilities, typically by using odors and visual cues for the conditioned stimuli. Here we asked whether honeybees could learn to distinguish between different magnitudes of the same type of stimulus, given as two speeds of air flux. By taking advantage of a novel automated system for administering PER experiments, we determined that the bees were highly successful when the lower air flux was rewarded and less successful when the higher flux was rewarded. Importantly, since our method includes AI-assisted analysis, we were able to consider subthreshold responses at a high temporal resolution; this analysis revealed patterns of rapid generalization and slowly acquired discrimination between the rewarded and unrewarded stimuli, as well as indications that the high air flux may have been mildly aversive. The learning curve for these mechanosensory stimuli, at least when the lower flux is rewarded, more closely mimics prior data from olfactory PER studies rather than visual ones, possibly in agreement with recent findings that the insect olfactory system is also sensitive to mechanosensory information. This work demonstrates a new modality to be used in PER experiments and lays the foundation for deeper exploration of honeybee cognitive processes when posed with complex learning challenges.

The adhesion class of G protein-coupled receptors (GPCRs) is the second largest family of GPCRs (33 members in humans). Adhesion GPCRs (aGPCRs) are defined by a large extracellular N-terminal region that is linked to a C-terminal seven transmembrane (7TM) domain via a GPCR-autoproteolysis inducing (GAIN) domain containing a GPCR proteolytic site (GPS). Most aGPCRs undergo autoproteolysis at the GPS motif, but the cleaved fragments stay closely associated, with the N-terminal fragment (NTF) bound to the 7TM of the C-terminal fragment (CTF). The NTFs of most aGPCRs contain domains known to be involved in cell-cell adhesion, while the CTFs are involved in classical G protein signaling, as well as other intracellular signaling. In this workshop report, we review the most recent findings on the biology, signaling mechanisms, and physiological functions of aGPCRs.

TRAAK is a membrane tension-activated K+ channel that has been associated through behavioral studies to mechanical nociception. We used specific monoclonal antibodies in mice to show that TRAAK is localized exclusively to nodes of Ranvier, the action potential propagating elements of myelinated nerve fibers. Approximately 80 percent of myelinated nerve fibers throughout the central and peripheral nervous system contain TRAAK in what is likely an all-nodes or no-nodes per axon fashion. TRAAK is not observed at the axon initial segment where action potentials are first generated. We used polyclonal antibodies, the TRAAK inhibitor RU2 and node clamp amplifiers to demonstrate the presence and functional properties of TRAAK in rat nerve fibers. TRAAK contributes to the leak K+ current in mammalian nerve fiber conduction by hyperpolarizing the resting membrane potential, thereby increasing Na+ channel availability for action potential propagation. We speculate on why nodes of Ranvier contain a mechanosensitive K+ channel.

TRAAK is a membrane tension-activated K+ channel that has been associated through behavioral studies to mechanical nociception. We used specific monoclonal antibodies in mice to show that TRAAK is localized exclusively to nodes of Ranvier, the action potential propagating elements of myelinated nerve fibers. Approximately 80 percent of myelinated nerve fibers throughout the central and peripheral nervous system contain TRAAK in what is likely an all-nodes or no-nodes per axon fashion. TRAAK is not observed at the axon initial segment where action potentials are first generated. We used polyclonal antibodies, the TRAAK inhibitor RU2 and node clamp amplifiers to demonstrate the presence and functional properties of TRAAK in rat nerve fibers. TRAAK contributes to the 'leak' K+ current in mammalian nerve fiber conduction by hyperpolarizing the resting membrane potential, thereby increasing Na+ channel availability for action potential propagation. We speculate on why nodes of Ranvier contain a mechanosensitive K+ channel.

This document is an editorial published in the journal Frontiers in Cell & Developmental Biology. It discusses the topic of tumor cell mechanosensitivity and its molecular basis. The editorial highlights the importance of physical signals in the microenvironment, such as matrix stiffness and tension, in influencing cancer cell behavior. The document also provides an overview of the articles included in the research topic, which cover various aspects of mechanobiology in cancer development and progression. The authors emphasize the need for further research on the role of mechanical properties in cancer cells and their interactions with other cell types. [Extracted from the article]

Members of both the Piezo and transmembrane channel-like (TMC) families are bona fide mammalian mechanotransducers. In a recent study, Zhang, Shao et al. discovered that TMC7, a non-mechanosensitive TMC, inhibits Piezo2-dependent mechanosensation, with implications for the importance of cellular context for Piezo2 channels in normal and pathological responses to mechanical pain. [ABSTRACT FROM AUTHOR]

Prolonged exposure to loud noise has been shown to affect inner ear sensory hair cells in a variety of deleterious manners, including damaging the stereocilia core. The damaged sites can be visualized as ‘gaps’ in phalloidin staining of F-actin, and the enrichment of monomeric actin at these sites, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments. Herein, we show that gaps in mouse auditory hair cells are largely repaired within 1 week of traumatic noise exposure through the incorporation of newly synthesized actin. We provide evidence that Xin actin binding repeat containing 2 (XIRP2) is required for the repair process and facilitates the enrichment of monomeric γ-actin at gaps. Recruitment of XIRP2 to stereocilia gaps and stress fiber strain sites in fibroblasts is force-dependent, mediated by a novel mechanosensor domain located in the C-terminus of XIRP2. Our study describes a novel process by which hair cells can recover from sublethal hair bundle damage and which may contribute to recovery from temporary hearing threshold shifts and the prevention of age-related hearing loss.