Mechanical forces are fundamental in cardiovascular biology, and deciphering the mechanisms by which they act remains a testing frontier in cardiovascular research. Here, we raise awareness of 2 ...recently discovered proteins, Piezo1 and Piezo2, which assemble as transmembrane triskelions to combine exquisite force sensing with regulated calcium influx. There is emerging evidence for their importance in endothelial shear stress sensing and secretion, NO generation, vascular tone, angiogenesis, atherosclerosis, vascular permeability and remodeling, blood pressure regulation, insulin sensitivity, exercise performance, and baroreceptor reflex, and there are early suggestions of relevance to cardiac fibroblasts and myocytes. Human genetic analysis points to significance in lymphatic disease, anemia, varicose veins, and potentially heart failure, hypertension, aneurysms, and stroke. These channels appear to be versatile force sensors, used creatively to inform various force-sensing situations. We discuss emergent concepts and controversies and suggest that the potential for new important understanding is substantial.
Piezo1 channels are newly discovered ion channels which have come to the fore as players in endothelial biology. They have a key role as sensors of shear stress, a frictional force which arises in ...vascular biology because of blood flow. Endothelial Piezo1 channels are critical in murine embryonic development, just after the heart starts to beat and drive blood into the nascent endothelial network. In contrast they are not critical at the adult stage but they are important for performance in whole body physical activity where they have a vascular bed‐specific effect to cause mesenteric resistance artery vasoconstriction, achieved through opposition to the vasodilatory mechanism of endothelium‐derived hyperpolarization. These are our first insights into the relevance of endothelial Piezo1 channels and there is clearly much more to be done to understand the significance and underlying molecular mechanisms. The suggestion that they constitute an exercise sensor by virtue of their shear stress‐sensing capability is intriguing and could open the way to better understanding of the molecular basis of the response to exercise and determination of how the health benefits of exercise arise. Enhanced Piezo1 channel activity has been demonstrated in response to the Yoda1 molecule and this suggests the possibility for developing tools which probe and manipulate this aspect of the exercise system. Whether such agents might progress to ‘exercise pills’ and whether the existence of such pills would be desirable are matters for further work and debate.
Piezo1 channels as sensors of exercise. Summary of the hypothesis for how Piezo1 channels act as sensors of exercise to redistribute blood flow and enhance whole body physical performance (Rode et al. ).
Piezo1 is a mechanosensitive cation channel with widespread physiological importance; however, its role in the heart is poorly understood. Cardiac fibroblasts help preserve myocardial integrity and ...play a key role in regulating its repair and remodeling following stress or injury. Here we investigated Piezo1 expression and function in cultured human and mouse cardiac fibroblasts. RT-PCR experiments confirmed that Piezo1 mRNA in cardiac fibroblasts is expressed at levels similar to those in endothelial cells. The results of a Fura-2 intracellular Ca2+ assay validated Piezo1 as a functional ion channel that is activated by its agonist, Yoda1. Yoda1-induced Ca2+ entry was inhibited by Piezo1 blockers (gadolinium and ruthenium red) and was reduced proportionally by siRNA-mediated Piezo1 knockdown or in murine Piezo1+/− cells. Results from cell-attached patch clamp recordings on human cardiac fibroblasts established that they contain mechanically activated ion channels and that their pressure responses are reduced by Piezo1 knockdown. Investigation of Yoda1 effects on selected remodeling genes indicated that Piezo1 activation increases both mRNA levels and protein secretion of IL-6, a pro-hypertrophic and profibrotic cytokine, in a Piezo1-dependent manner. Moreover, Piezo1 knockdown reduced basal IL-6 expression from cells cultured on softer collagen-coated substrates. Multiplex kinase activity profiling combined with kinase inhibitor experiments and phosphospecific immunoblotting established that Piezo1 activation stimulates IL-6 secretion via the p38 mitogen-activated protein kinase downstream of Ca2+ entry. In summary, cardiac fibroblasts express mechanically activated Piezo1 channels coupled to secretion of the paracrine signaling molecule IL-6. Piezo1 may therefore be important in regulating cardiac remodeling.
Mammalian biology adapts to physical activity but the molecular mechanisms sensing the activity remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force to enable ...vascular development. Here, we address Piezo1 in adult endothelium, the major control site in physical activity. Mice without endothelial Piezo1 lack obvious phenotype but close inspection reveals a specific effect on endothelium-dependent relaxation in mesenteric resistance artery. Strikingly, the Piezo1 is required for elevated blood pressure during whole body physical activity but not blood pressure during inactivity. Piezo1 is responsible for flow-sensitive non-inactivating non-selective cationic channels which depolarize the membrane potential. As fluid flow increases, depolarization increases to activate voltage-gated Ca
channels in the adjacent vascular smooth muscle cells, causing vasoconstriction. Physical performance is compromised in mice which lack endothelial Piezo1 and there is weight loss after sustained activity. The data suggest that Piezo1 channels sense physical activity to advantageously reset vascular control.The mechanisms that regulate the body's response to exercise are poorly understood. Here, Rode et al. show that the mechanically activated cation channel Piezo1 is a molecular sensor of physical exercise in the endothelium that triggers endothelial communication to mesenteric vessel muscle cells, leading to vasoconstriction.
Transient receptor potential canonical (TRPC) proteins assemble to form homo- or heterotetrameric, nonselective cation channels permeable to K
+
, Na
+
, and Ca
2+
. TRPC channels are thought to act ...as complex integrators of physical and chemical environmental stimuli. Although the understanding of essential physiological roles of TRPC channels is incomplete, their implication in various pathological mechanisms and conditions of the nervous system, kidneys, and cardiovascular system in combination with the lack of major adverse effects of TRPC knockout or TRPC channel inhibition is driving the search of TRPC channel modulators as potential therapeutics. Here, we review the most promising small-molecule TRPC channel modulators, the understanding of their mode of action, and their potential in the study and treatment of cardiovascular and metabolic disease.
Polymer networks are complex systems consisting of molecular components. Whereas the properties of the individual components are typically well understood by most chemists, translating that chemical ...insight into polymer networks themselves is limited by the statistical and poorly defined nature of network structures. As a result, it is challenging, if not currently impossible, to extrapolate from the molecular behavior of components to the full range of performance and properties of the entire polymer network. Polymer networks therefore present an unrealized, important, and interdisciplinary opportunity to exert molecular-level, chemical control on material macroscopic properties. A barrier to sophisticated molecular approaches to polymer networks is that the techniques for characterizing the molecular structure of networks are often unfamiliar to many scientists. Here, we present a critical overview of the current characterization techniques available to understand the relation between the molecular properties and the resulting performance and behavior of polymer networks, in the absence of added fillers. We highlight the methods available to characterize the chemistry and molecular-level properties of individual polymer strands and junctions, the gelation process by which strands form networks, the structure of the resulting network, and the dynamics and mechanics of the final material. The purpose is not to serve as a detailed manual for conducting these measurements but rather to unify the underlying principles, point out remaining challenges, and provide a concise overview by which chemists can plan characterization strategies that suit their research objectives. Because polymer networks cannot often be sufficiently characterized with a single method, strategic combinations of multiple techniques are typically required for their molecular characterization.
Transient receptor potential canonical (TRPC) proteins assemble to form ion channels that enable influx of calcium and sodium ions into cells. There are 6 TRPC proteins in humans but more TRPC ...channels may arise through heteromerization among TRPCs and other types of TRP protein. They are widely expressed and have multiple functions throughout the peripheral and central systems of the body. This review summarizes current knowledge of the characteristics of TRPC channels and discusses principles by which the channels operate. Modulators of the channels include lipids, redox factors, and agonists at G-protein and tyrosine kinase receptors. The channels enable coupling between these factors and the calcium ion, which is a master intracellular regulator of multiple cell functions. In the context of this information the review gives specific consideration to TRPC channels in vascular cells, which include endothelial cells, vascular smooth muscle cells, perivascular adipocytes, and cells of the hematopoietic lineage. It is discussed that the channels may have most significance as drivers of change when there is strain or insult in physiology or disease. The TRPC proteins constitute a substantial and important group of calcium-permeable channels. They remain enigmatic but there is increasing understanding of their properties and recognition of their importance in the vasculature as well as in other systems such as the myocardium. (Circ J 2013; 77: 570–579)
Piezo1 is a mechanosensitive channel involved in many cellular functions and responsible for sensing shear stress and pressure forces in cells. Piezo1 has a unique trilobed topology with a curved ...membrane region in the closed state. It has been suggested that upon activation Piezo1 adopts a flattened conformation, but the molecular and structural changes underpinning the Piezo1 gating and opening mechanisms and how the channel senses forces in the membrane remain elusive. Here, we used molecular dynamics simulations to reveal the structural rearrangements that occur when Piezo1 moves from a closed to an open state in response to increased mechanical tension applied to a model membrane. We find that membrane stretching causes Piezo1 to flatten and expand its blade region, resulting in tilting and lateral movement of the pore-lining transmembrane helices 37 and 38. This is associated with the opening of the channel and movement of lipids out of the pore region. Our results reveal that because of the rather loose packing of Piezo1 pore region, movement of the lipids outside the pore region is critical for the opening of the pore. Our simulations also suggest synchronous flattening of the Piezo1 blades during Piezo1 activation. The flattened structure lifts the C-terminal extracellular domain up, exposing it more to the extracellular space. Our studies support the idea that it is the blade region of Piezo1 that senses tension in the membrane because pore opening failed in the absence of the blades. Additionally, our simulations reveal that upon opening, water molecules occupy lateral fenestrations in the cytosolic region of Piezo1, which might be likely paths for ion permeation. Our results provide a model for how mechanical force opens the Piezo1 channel and thus how it might couple mechanical force to biological response.
Current therapies for common types of cancer such as renal cell cancer are often ineffective and unspecific, and novel pharmacological targets and approaches are in high demand. Here we show the ...unexpected possibility for the rapid and selective killing of renal cancer cells through activation of calcium‐permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (−)‐englerin A. This compound was found to be a highly efficient, fast‐acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels. TRPC4/5 activation through a high‐affinity extracellular (−)‐englerin A binding site may open up novel opportunities for drug discovery aimed at renal cancer.
Natural born killer: The sesquiterpene (−)‐englerin A rapidly and selectively kills renal cancer cells through activation of calcium‐permeable nonselective transient receptor potential canonical (TRPC) calcium channels. It is a highly efficient, fast‐acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels (PM=plasma membrane).
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