Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

Abstract

Discovery of Piezo channels and the reporting of their sensitivity to the inhibitor GsMTx4 were important milestones in the study of non-selective cationic mechanosensitive channels (MSCs) in normal physiology and pathogenesis. GsMTx4 had been used for years to investigate the functional role of cationic MSCs, especially in muscle tissue, but with little understanding of its target or inhibitory mechanism. The sensitivity of Piezo channels to bilayer stress and its robust mechanosensitivity when expressed in heterologous systems were keys to determining GsMTx4’s mechanism of action. However, questions remain regarding Piezo’s role in muscle function due to the non-selective nature of GsMTx4 inhibition toward membrane mechanoenzymes and the implication of MCS channel types by genetic knockdown. Evidence supporting Piezo like activity, at least in the developmental stages of muscle, is presented. While the MSC targets of GsMTx4 in muscle pathology are unclear, its muscle protective effects are clearly demonstrated in two recent in situ studies on normal cardiomyocytes and dystrophic skeletal muscle. The muscle protective function may be due to the combined effect of GsMTx4’s inhibitory action on cationic MSCs like Piezo and TRP, and its potentiation of repolarizing K+ selective MSCs like K2P and SAKCa. Paradoxically, the potent in vitro action of GsMTx4 on many physiological functions seems to conflict with its lack of in situ side-effects on normal animal physiology. Future investigations into cytoskeletal control of sarcolemma mechanics and the suspected inclusion of MSCs in membrane micro/nano sized domains with distinct mechanical properties will aide our understanding of this dichotomy.

Mechanotransduction Channel Piezo is Widely Expressed in the Spider, Cupiennius Salei, Mechanosensory Neurons and Central Nervous Systems

“…This may be explained by the replacement of residues E2495 and E2496 that are critical for mouse Piezo Ruthenium Red sensitivity, with E2466 and D2467 in Drosophila Piezo [59] and D2502 and D2503 in CsPiezo. GsMTx4 is a more speci c blocker of mechanosensitive cation channels including Piezos [60]. Although voltage activated K + and Na + channels are also sensitive to the L-form of GsMTx4 at relatively high concentrations [61], lower concentrations of its D-form, which was used here, are unlikely to have signi cant effects on voltage gated channels [62].…”

The peripheral origin of tap-induced muscle contraction revealed by multi-electrode surface electromyography in human vastus medialis

“…It may be speculated that the abrupt sarcolemmal deformation produced by the percussion opens mechano-sensitive ion channels 27 and activates depolarizing currents that excite the affected muscle fibres, similarly to what has been described for nerve fibres 28,29 . In support of this hypothesis is the abundance of mechano-sensitive channels on the sarcolemma, belonging to the transient receptor potential (TRP) and to the Piezo families 30,31 . They are considered to be sensitive to the force transmitted by the lipid bilayer of the cell membrane 32 and, in particular, to shear stress and stretch of the membrane 33 .…”

“…In the skeletal muscle, these non-selective cation channels are considered to have a role in different processes such as muscle development and contrast to muscle fatigue. In addition, due to their contribution to calcium inflow they have been implicated in the alteration of the contractile machinery in muscle dystrophies 30,31,34 . In vascular smooth muscle, stretch-activated mechano-sensitive cation channels are considered to mediate the membrane depolarization that precedes the contraction, in the myogenic response (the vessel constrictory response to increased transmural pressure) 35 .…”

Integrating Biophysics in Toxicology

“…modification of membrane curvature/tension [20,21]; ii) re-distribution of transmembrane proteins [22,23]; iii) modulation of ionic fluxes through mechanosensitive ion channels [24][25][26][27]; iv) deformation of cyto-nucleoskeletal elements [28,29]; and v) reorganization of intracellular organelles [30][31][32].…”