The mechanism by which Piezo acts in

The mechanism by which Piezo1 acts in the regulation of RBC volume is not firmly established. Its curved structure implies that it is activated by an increase in membrane tension (11), a mechanism indicated by electrophysiological measurements (16). However, the RBC membrane mechanics at its physiological reduced volume of around 0.6 are governed by the bending of its bilayer part and by the shear elasticity of its spectrin network, exhibiting a relatively small stretching constant of its bonds (17). Lateral membrane tension is thus much smaller than that under the conditions of the electrophysiological experiment (16). RBCs exhibit a flickering phenomenon (18), which is further evidence for the membrane not being under high tension. Assuming that mechanosensitive dexamethasone acetate receptor can change membrane permeability in response to any kind of mechanical stimulus, it is of interest to search for other possible mechanisms of Piezo1 action. The curved structure of the Piezo1 homotrimer (10, 11, 12, 13) supports the possibility that it could also act through its sensitivity to membrane curvature. This idea is supported by the large size of Piezo1, which is an important factor in determining the strength of the curvature-dependent interaction of membrane inclusions with the surrounding phospholipid membrane moiety (19). The curvature-dependent permeability of Piezo1 is implied by recent observations on RBCs embedded in a gel, which was then compressed, causing them to deform (20). This led to an increased metabolic rate and increased cation (using cesium ions as a replacement for potassium ions) efflux. Further indirect evidence for the curvature-based mechanism of Piezo1 action is its inhibition by the spider venom peptide GsMTx4, which acts by intercalating into the lipid layers of the RBC membrane, thus affecting its nonspecific curvature status (21). In this work, we have developed a model of RBC volume regulation by the Piezo1-Gárdos channel system based on the thesis that Piezo1 channel permeability depends on membrane curvature and thus on RBC shape. The central idea is that Piezo1 senses the shape of the RBC discocyte, and because it is different at different cell volumes, the fraction of open Piezo1 channels depends on RBC volume. Our main purpose here is to reveal the principle of the corresponding Piezo1 operation. We therefore restrict the model to that part of the RBC pump-leak system that involves the homeostasis of K+ ions. The corresponding simplified picture of the real RBC system is described in RBC Properties Essential for Establishing its Volume. In particular, it is shown how the fraction of open channels relates to the RBC volume. In A Possible Mechanism for the Effect of RBC Shape on Piezo1 Channel Permeability (i.e., the core section of this work), it is shown that the fraction of open Piezo1 channels depends on the RBC reduced volume by assuming that Piezo1 possesses open and closed conformations whose interactions with the surrounding membrane are curvature dependent in different ways. This dependence will be applied to discocyte shapes at different RBC reduced volumes. A Possible Mechanism for the Effect of RBC Shape on Piezo1 Channel Permeability will therefore include a description of the membrane curvature characteristics of these shapes. The proposed model will be in Model Predictions and their Support by Existing Experimental Evidence, applied to describe some observations that support the proposed mechanism of RBC volume regulation. Its implications will be shown to be consistent with the differences in the behavior of normal RBCs and of those of Piezo1 knockout mice (14). It will also be shown that the described mechanism explains why RBCs with larger membrane areas (A) also have, on average, larger volumes (V) (22, 23, 24). The Discussion includes a description of some possible generalizations of the described mechanism.
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