Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology.
TLDR
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, but evidence supporting Piezo like activity, at least in the developmental stages of muscle, is presented.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.read more
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References
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Journal ArticleDOI
Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels
Bertrand Coste,Jayanti Mathur,Manuela Schmidt,Taryn J. Earley,Sanjeev S. Ranade,Matt Petrus,Adrienne E. Dubin,Ardem Patapoutian,Ardem Patapoutian +8 more
TL;DR: Two genes that encode proteins, Piezo1 and Piezo2, are identified, which are required for mechanically stimulated cation conductance in these cells and in cultured dorsal root ganglion neurons, and it is proposed that Piezos are components of MA cation channels.
Journal ArticleDOI
Structure of the TRPV1 ion channel determined by electron cryo-microscopy
TL;DR: In this article, a high-resolution electron cryo-microscopy structure of the rat transient receptor potential (TRP) channel in its closed state is presented; the overall structure of this ion channel is found to share some common features with voltage-gated ion channels, although several unique, TRP-specific features are also characterized.
Journal ArticleDOI
Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle.
F. Guharay,Frederick Sachs +1 more
TL;DR: The membrane of tissue‐cultured chick pectoral muscle contains an ionic channel which is activated by membrane stretch, and appears to gather force from a large area of membrane, probably by a cytochalasin‐resistant cytoskeletal network.
Journal ArticleDOI
Piezo proteins are pore-forming subunits of mechanically activated channels
Bertrand Coste,Bailong Xiao,Jose S. Santos,Ruhma Syeda,Jörg Grandl,Jörg Grandl,Kathryn S. R. Spencer,Sung-Eun Kim,Manuela Schmidt,Jayanti Mathur,Adrienne E. Dubin,Mauricio Montal,Ardem Patapoutian,Ardem Patapoutian +13 more
TL;DR: It is shown that Drosophila melanogaster Piezo (DmPiezo, also called CG8486) also induces mechanically activated currents in cells, but through channels with remarkably distinct pore properties including sensitivity to the pore blocker ruthenium red and single channel conductances, demonstrating that Piezo proteins are an evolutionarily conserved ion channel family involved in mechanotransduction.
Journal ArticleDOI
TRPC1 forms the stretch-activated cation channel in vertebrate cells
TL;DR: A membrane-protein fraction that reconstituted high MscCa activity and showed an abundance of a protein that had a relative molecular mass of 80,000 (Mr 80K) indicate that TRPC1 is a component of the vertebrate MSCCa, which is gated by tension developed in the lipid bilayer, as is the case in various prokaryotic mechanosensitive (Ms) channels.