On the gating of mechanosensitive channels by fluid shear stress

Mechanosensation is an important process in biological fluid-structure interaction. To understand the biophysics underlying mechanosensation, it is essential to quantify the correlation between membrane deformation, membrane tension, external fluid shear stress, and conformation of mechanosensitive (MS) channels. Smoothed dissipative particle dynamics (SDPD) simulations of vesicle/cell in three types of flow configurations are conducted to calculate the tension in lipid membrane due to fluid shear stress from the surrounding viscous flow. In combination with a simple continuum model for an MS channel, SDPD simulation results suggest that shearing adhered vesicles/cells is more effective to induce membrane tension sufficient to stretch MS channels open than a free shear flow or a constrictive channel flow. In addition, we incorporate the bilayer-cytoskeletal interaction in a two-component model to probe the effects of a cytoskeletal network on the gating of MS channels.

Magnesium permeation through mechanosensitive channels:single-current measurements

Compelling evidence shows that intracellular free magnesium [Mg^2＋]i may be a critical regulator of cell activity in eukaryotes. However, membrane transport mechanisms mediating Mg^2＋ influx in mammalian cells are poorly understood. Here, we show that mechanosensitive （MS） cationic channels activated by stretch are permeable for Mg^2＋ ions at different extracellular concentrations including physiological ones. Single-channel currents were recorded from cell-attached and inside-out patches on K562 leukaemia cells at various concentrations of MgCl2 when Mg^2＋ was the only available carrier of inward currents. At 2 mM Mg^2＋, inward mechanogated currents representing Mg^2＋ influx through MS channels corresponded to the unitary conductance of about 5 pS. At higher Mg^2＋ levels, only slight increase of single-channel currents and conductance occurred, implying that Mg^2＋ permeation through MS channels is characterized by strong saturation. At 20 and 90 mM Mg^2＋, mean conductance values for inward currents carried by Mg^2＋ were rather similar, being equal to 6.8 ± 0.5 and 6.4 ± 0.5 pS, respectively. The estimation of the channel-selective permeability according to constant field equation is obviously limited due to saturation effects. We conclude that the detection of single currents is the main evidence for Mg^2＋ permeation through membrane channels activated by stretch. Our single-current measurements document Mg^2＋ influx through MS channels in the plasma membrane of leukaemia cells.

Mechanical force and cytoplasmic Ca^(2+) activate mechanosensitive BK channel in parallel

BK channels are widely expressed in both excitable and non-excitable cells and known to be involved in many physiological processes,such as vascular smooth tone regulation,neuronal firing and endocrine cell secretion[1].Recently, the BK channels have

Effects of Acute Mechanical Stretch on the Expression of Mechanosensitive Potassium Channel TREK-1 in Rat Left Ventricle

To explore the role of mechanosensitive potassium channel TREK-1, Western blot analysis was used to investigate the expression changes of TREK-1 in left ventricle in acute mechanically stretched heart. Forty Wistar rats were randomly divided into 8 groups （n=5 in each group）, subject to single Langendorff perfusion for 0, 30, 60, 120 min and acute mechanical stretch for 0, 30, 60, 120 min respectively. With Langendorff apparatus, an acute mechanically stretched heart model was established. There was no significant difference in the expression of TREK-1 among single Langendorff perfusion groups （P〉0.05）. As compared to non-stretched Langendorff-perfused heart, only the expression of TREK-1 in acute mechanically stretched heart （120 min） was greatly increased （P〈0.05）. This result suggested that some course of mechanical stretch could up-regulate the expression of TREK-1 in left ventricle. TREK-1 might play an important role in mechanoelectric feedback, so it could reduce the occurrence of arrhythmia that was induced by extra mechanical stretch.

Tuning the mechanosensitivity of a BK channel by changing the linker length

Some large-conductance Ca^2＋ and voltage-activated K^＋（BK） channels are activated by membrane stretch. However, the mechanism of mechano-gating of the BK channels is still not well understood. Previous studies have led to the proposal that the linker-gating ring complex functions as a passive spring, transducing the force generated by intracellular Ca^2＋ to the gate to open the channel. This raises the question as to whether membrane stretch is also transmitted to the gate of mechanosensitive （MS） BK channels via the linker-gating complex. To study this, we changed the linker length in the stretch-activated BK channel （SAKCaC）, and examined the effect of membrane stretch on the gating of the resultant mutant channels. Shortening the linker increased, whereas extending the linker reduced, the channel mechanosensitivity both in the presence and in the absence of intracellular Ca^2＋. However, the voltage and Ca^2＋ sensitivities were not significantly altered by membrane stretch. Furthermore, the SAKCaC became less sensitive to membrane stretch at relatively high intracellular Ca^2＋ concentrations or membrane depolarization. These observations suggest that once the channel is in the open-state conformation, tension on the spring is partially released and membrane stretch is less effective. Our results are consistent with the idea that membrane stretch is transferred to the gate via the linker-gating ring complex of the MS BK channels.

Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain

Post-amputation pain causes great sufering to amputees,but still no efective drugs are available due to its elusive mechanisms.Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump efectively relieves the phantom pain aficting patients after amputation.This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain(CPAP).However,the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery.In this study,we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infltrated into the dorsal root ganglion(DRG)neurons worked synergistically to promote CPAP.Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG,and the expression of TMEM63A increased signifcantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer(TNT).Behavioral tests showed that the mechanical,heat,and cold sensitivity were not afected in the Tmem63a-/-mice in the naïve state,suggesting the basal pain was not afected.In the infammatory and post-amputation state,the mechanical allodynia but not the heat hyperalgesia or cold allodynia was signifcantly decreased in Tmem63a-/-mice.Further study showed that there was severe neuronal injury and macrophage infltration in the DRG,tibial nerve,residual stump,and the neuromalike structure of the TNT mouse model,Consistent with this,expression of the pro-infammatory cytokines TNFα,IL-6,and IL-1βall increased dramatically in the DRG.Interestingly,the deletion of Tmem63a signifcantly reduced the macrophage infltration in the DRG but not in the tibial nerve stump.Furthermore,the ablation of macrophages signifcantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model,indicating an interaction between nociceptors and macrophages,and that these two factors gang up together to regulate the formation of CPAP.This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.

Recent advancement of sonogenetics:A promising noninvasive cellular manipulation by ultrasound

Recent advancements in biomedical research have underscored the importance of noninvasive cellular manipulation techniques.Sonogenetics,a method that uses genetic engineering to produce ultrasound-sensitive proteins in target cells,is gaining prominence along with optogenetics,electrogenetics,and magnetogenetics.Upon stimulation with ultrasound,these proteins trigger a cascade of cellular activities and functions.Unlike traditional ultrasound modalities,sonogenetics offers enhanced spatial selectivity,improving precision and safety in disease treatment.This technology broadens the scope of non-surgical interventions across a wide range of clinical research and therapeutic applications,including neuromodulation,oncologic treatments,stem cell therapy,and beyond.Although current literature predominantly emphasizes ultrasonic neuromodulation,this review offers a comprehensive exploration of sonogenetics.We discuss ultrasound properties,the specific ultrasound-sensitive proteins employed in sonogenetics,and the technique’s potential in managing conditions such as neurological disorders,cancer,and ophthalmic diseases,and in stem cell therapies.Our objective is to stimulate fresh perspectives for further research in this promising field.

A gain-of-function mutation in Msl10 triggers cell death and wound-induced hyperaccumulation of jasmonic acid in Arabidopsis

Jasmonates（JAs） are rapidly induced after wounding and act as key regulators for wound induced signaling pathway. However, what perceives the wound signal and how that triggers JA biosynthesis remains poorly understood. To identify components involved in Arabidopsis wound and JA signaling pathway, we screened for mutants with abnormal expression of a luciferase reporter, which is under the control of a wound-responsive promoter of an ethylene response factor（ERF） transcription factor gene, RAP2.6（Related to APetala 2.6）.The rea1（RAP2.6 expresser in shoot apex） mutant constitutively expressed the RAP2.6-LUC reporter gene in young leaves.Along with the typical JA phenotypes including shorter petioles,loss of apical dominance, accumulation of anthocyanin pigments and constitutive expression of JA response gene, rea1 plants also displayed cell death and accumulated high levels of JA in response to wounding. The phenotype of rea1 mutant is caused by a gain-of-function mutation in the C-terminus of a mechanosensitive ion channel MscS-like 10（MSL10）. MSL10 is localized in the plasma membrane and is expressed predominantly in root tip, shoot apex and vascular tissues. These results suggest that MSL10 is involved in the wound-triggered early signal transduction pathway and possibly in regulating the positive feedback synthesis of JA.