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Mechanically Activated Ion Channels

2015; Cell Press; Volume: 87; Issue: 6 Linguagem: Inglês

10.1016/j.neuron.2015.08.032

1097-4199

Sanjeev S. Ranade, Ruhma Syeda, Ardem Patapoutian,

Cardiac electrophysiology and arrhythmias

Mechanotransduction, the conversion of physical forces into biochemical signals, is essential for various physiological processes such as the conscious sensations of touch and hearing, and the unconscious sensation of blood flow. Mechanically activated (MA) ion channels have been proposed as sensors of physical force, but the identity of these channels and an understanding of how mechanical force is transduced has remained elusive. A number of recent studies on previously known ion channels along with the identification of novel MA ion channels have greatly transformed our understanding of touch and hearing in both vertebrates and invertebrates. Here, we present an updated review of eukaryotic ion channel families that have been implicated in mechanotransduction processes and evaluate the qualifications of the candidate genes according to specified criteria. We then discuss the proposed gating models for MA ion channels and highlight recent structural studies of mechanosensitive potassium channels. Mechanotransduction, the conversion of physical forces into biochemical signals, is essential for various physiological processes such as the conscious sensations of touch and hearing, and the unconscious sensation of blood flow. Mechanically activated (MA) ion channels have been proposed as sensors of physical force, but the identity of these channels and an understanding of how mechanical force is transduced has remained elusive. A number of recent studies on previously known ion channels along with the identification of novel MA ion channels have greatly transformed our understanding of touch and hearing in both vertebrates and invertebrates. Here, we present an updated review of eukaryotic ion channel families that have been implicated in mechanotransduction processes and evaluate the qualifications of the candidate genes according to specified criteria. We then discuss the proposed gating models for MA ion channels and highlight recent structural studies of mechanosensitive potassium channels. Our sensory system allows us to perceive the external world. Each of the five senses contains a unique receptor cell in which integral membrane proteins, such as G protein-coupled receptors (GPCRs) or ion channels, convert external stimuli into electrical signals that are relayed to our brain. For example, rod cells in the eye express high levels of rhodopsin, a GPCR conjugated to a chromophore and activated by photons of light (Figure 1A). Olfactory epithelial cells contain a diverse array of GPCRs that are activated by volatile small molecules in the air and allow us to sense smells (Figure 1B). Similarly, GPCRs expressed in taste receptor cells, are activated by chemicals in the food that we eat (Figure 1C). Unlike these three senses, our ability to feel touch and hear sounds comes from the activation of ion channels that respond to mechanical forces such as vibration, indentation, gravity, and sound waves (Figures 1D and 1E). Epithelial hair cells contain a stereocilia bundle that is inter-connected by tip links. The mechanical force imparted by sound waves bends the stereocilia and pulls on the tip links. The strain induced by tip link pulling is thought to open a mechanically activated ion channel complex (Figure 1D). The peripheral endings of somatosensory neurons consist of either free nerve terminals thought to detect noxious stimuli or specialized terminals that detect innocuous physical stimuli (Figure 1E). Fundamental insight into the function of sensory systems has been gained by the identification and characterization of the receptor genes for each system. Partly because it is expressed in high enough levels to facilitate biochemical analysis, rhodopsin was the first sensory receptor gene to be identified and sequenced (Hargrave et al., 1983Hargrave P.A. McDowell J.H. Curtis D.R. Wang J.K. Juszczak E. Fong S.L. Rao J.K. Argos P. The structure of bovine rhodopsin.Biophys. Struct. Mech. 1983; 9: 235-244Crossref PubMed Scopus (0) Google Scholar, Nathans and Hogness, 1983Nathans J. Hogness D.S. Isolation, sequence analysis, and intron-exon arrangement of the gene encoding bovine rhodopsin.Cell. 1983; 34: 807-814Abstract Full Text PDF PubMed Scopus (0) Google Scholar). Advances in molecular cloning techniques and new strategies to identify genes based on sequence similarities to known GPCRs led to the landmark discovery of a multi-gene GPCR family of olfactory receptors, as well as the identification of receptors for taste (Buck and Axel, 1991Buck L. Axel R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition.Cell. 1991; 65: 175-187Abstract Full Text PDF PubMed Scopus (2918) Google Scholar, Hoon et al., 1999Hoon M.A. Adler E. Lindemeier J. Battey J.F. Ryba N.J. Zuker C.S. Putative mammalian taste receptors: a class of taste-specific GPCRs with distinct topographic selectivity.Cell. 1999; 96: 541-551Abstract Full Text Full Text PDF PubMed Google Scholar). Electrophysiology recordings of auditory receptor cells were the first experiments to suggest the existence of ion channels that could be directly activated by mechanical force (Corey and Hudspeth, 1979Corey D.P. Hudspeth A.J. Response latency of vertebrate hair cells.Biophys. J. 1979; 26: 499-506Abstract Full Text PDF PubMed Google Scholar). Stretch-activated cation channels were then recorded in other non-sensory tissues, such as skeletal muscle cells (Guharay and Sachs, 1984Guharay F. Sachs F. Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle.J. Physiol. 1984; 352: 685-701Crossref PubMed Google Scholar). Unlike the structural similarities of GPCRs, ion channels vary greatly in sequence and function. Indeed, the only common structural feature of ion channels is that they all contain a minimum of two transmembrane domains. Whereas rhodopsin is highly enriched in rod cells, mechanosensitive ion channels are usually expressed at low levels in endogenous cells and may be associated in complexes with auxiliary proteins (Arnadóttir and Chalfie, 2010Arnadóttir J. Chalfie M. Eukaryotic mechanosensitive channels.Annu. Rev. Biophys. 2010; 39: 111-137Crossref PubMed Scopus (163) Google Scholar). These limitations have delayed the identification of mechanically activated ion channels compared to other receptors. Indeed, many of the candidate mechanosensitive channels in vertebrates and invertebrates were ultimately identified by genetic or genomic screens, and not via biochemical or homology approaches. It has previously been suggested that certain qualifications must be met in order for a candidate ion channel to be considered a transducer of mechanical force (Arnadóttir and Chalfie, 2010Arnadóttir J. Chalfie M. Eukaryotic mechanosensitive channels.Annu. Rev. Biophys. 2010; 39: 111-137Crossref PubMed Scopus (163) Google Scholar, Christensen and Corey, 2007Christensen A.P. Corey D.P. TRP channels in mechanosensation: direct or indirect activation?.Nat. Rev. Neurosci. 2007; 8: 510-521Crossref PubMed Scopus (251) Google Scholar). The candidate gene must be expressed in a mechanosensitive cell and loss of that gene should abolish mechanosensitivity without affecting the development of that cell. Ideally, expression of the candidate gene should be sufficient to confer mechanosensitivity to a naive cell and deletion of the gene in a model organism should lead to deficits in mechanotransduction processes in vivo. Further characterization includes validation that the candidate gene encodes for the pore-forming subunit, either by engineering point mutations that alter ion selectivity and conductance or by structural analysis. If auxiliary subunits are not involved in gating, the candidate ion channel should retain mechanosensitivity when purified and reconstituted into artificial lipid bilayers. The identification of receptors remains a critical first step toward an understanding of mechanotransduction processes in vivo. Indeed, the characterization of temperature-activated transient receptor potential ion channels has greatly advanced our understanding of thermosensation in both vertebrates and invertebrates (Caterina et al., 1997Caterina M.J. Schumacher M.A. Tominaga M. Rosen T.A. Levine J.D. Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature. 1997; 389: 816-824Crossref PubMed Scopus (5337) Google Scholar, Peier et al., 2002Peier A.M. Moqrich A. Hergarden A.C. Reeve A.J. Andersson D.A. Story G.M. Earley T.J. Dragoni I. McIntyre P. Bevan S. Patapoutian A. A TRP channel that senses cold stimuli and menthol.Cell. 2002; 108: 705-715Abstract Full Text Full Text PDF PubMed Scopus (1249) Google Scholar). Only a few candidate mechanosensitive ion channels have been discovered that meet all of the prerequisite qualifications. However, over the past few years, a number of advances have been made through the identification of new ion channels, such as the Piezo family, as well as the elucidation of high-resolution crystal structures of mechanosensitive potassium channels. In this review, we summarize research into eukaryotic ion channel families that contain candidate genes implicated as mechanically activated ion channels. While we focus primarily on the sensory systems of touch and hearing, it is important to note that mechanotransduction processes extend to numerous physiological systems including cardiovascular, pulmonary, vestibular, baroreceptor reflex etc. (Teng et al., 2015Teng J. Loukin S. Anishkin A. Kung C. The force-from-lipid (FFL) principle of mechanosensitivity, at large and in elements.Pflugers Arch. 2015; 467: 27-37Crossref PubMed Google Scholar). Mechanosensitive ion channels are expressed in nearly all cell types, including commonly studied heterologous expression systems like the Neuro2A cell line from which Piezo1 was identified (Coste et al., 2010Coste B. Mathur J. Schmidt M. Earley T.J. Ranade S. Petrus M.J. Dubin A.E. Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels.Science. 2010; 330: 55-60Crossref PubMed Scopus (430) Google Scholar). Although we describe eukaryotic channels in greater detail, we also present an analysis of studies from bacterial MscL and MscS ion channels in the context of two general models for how physical forces can gate mechanically activated ion channels. Recent studies of K2P potassium channels have shown that the principles established for gating prokaryotic mechanosensitive ion channels are more similar to eukaryotic channels than previously appreciated. The development of assays to probe the function of mechanically activated ion channels has played an important role in the identification and characterization of these elusive ion channels. Mechanically activated ion channels can respond to a diverse range of physical forces such as vibration, stretch, or sound waves (Delmas et al., 2011Delmas P. Hao J. Rodat-Despoix L. Molecular mechanisms of mechanotransduction in mammalian sensory neurons.Nat. Rev. Neurosci. 2011; 12: 139-153Crossref PubMed Scopus (161) Google Scholar). Numerous in vitro and ex vivo assays have been developed to apply various forms of mechanical force either to isolated cells or to intact tissue preparations. Ion channel activation is usually recorded by directly measuring ion flow across the lipid bilayer using patch clamp electrophysiology of isolated cells or by recording action potential firing activity from nerve fibers in intact tissue preparations (Reeh, 1986Reeh P.W. Sensory receptors in mammalian skin in an in vitro preparation.Neurosci. Lett. 1986; 66: 141-146Crossref PubMed Scopus (0) Google Scholar). Along with electrophysiology techniques, calcium sensitive fluorescent small molecules such as Fura-2 or genetically encoded calcium indicator (GECI) proteins have also been used to measure the activity of mechanically activated cation channels (Tian et al., 2009Tian L. Hires S.A. Mao T. Huber D. Chiappe M.E. Chalasani S.H. Petreanu L. Akerboom J. McKinney S.A. Schreiter E.R. et al.Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators.Nat. Methods. 2009; 6: 875-881Crossref PubMed Scopus (948) Google Scholar, Tsien, 1989Tsien R.Y. Fluorescent probes of cell signaling.Annu. Rev. Neurosci. 1989; 12: 227-253Crossref PubMed Google Scholar). The application of mechanical force to isolated cells is achieved primarily by fluid shear stress, membrane stretch or membrane indentation with a glass pipette (Figures 2A–2D). Membrane stretch can also be applied to purified, lipid-solubilized ion channels reconstituted into proteoliposomes (Brohawn et al., 2014bBrohawn S.G. Su Z. MacKinnon R. Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels.Proc. Natl. Acad. Sci. USA. 2014; 111: 3614-3619Crossref PubMed Scopus (86) Google Scholar). Each of these potentially distinct mechanical stimuli is thought to be relevant for specific cell types. For example, endothelial cells experience shear stress; muscles cells, stretch; somatosensory neurons, membrane indentation. Both fluid shear stress and membrane indentation have also been used to apply mechanical force to the stereocilia bundle of isolated epithelial hair cells (Figures 2E and 2F) (Fettiplace and Kim, 2014Fettiplace R. Kim K.X. The physiology of mechanoelectrical transduction channels in hearing.Physiol. Rev. 2014; 94: 951-986Crossref PubMed Scopus (56) Google Scholar). Whereas mechanical indentation is used primarily to deflect the stereocilia bundle in one direction, fluid shear stress can deflect the stereocilia bundle in both forward and reverse directions (Kim et al., 2013Kim K.X. Beurg M. Hackney C.M. Furness D.N. Mahendrasingam S. Fettiplace R. The role of transmembrane channel-like proteins in the operation of hair cell mechanotransducer channels.J. Gen. Physiol. 2013; 142: 493-505Crossref PubMed Scopus (52) Google Scholar). Interestingly, changes to osmotic potentials can induce cell swelling and can also exert mechanical strain onto the cell membrane (Figure 2G). However, cellular swelling due to changes in osmotic potentials is slower and less uniform compared to other mechanical forces such as stretch or membrane indentation, and likely involves numerous compensatory cytoskeletal changes (Sachs, 2010Sachs F. Stretch-activated ion channels: what are they?.Physiology (Bethesda). 2010; 25: 50-56Crossref PubMed Scopus (141) Google Scholar). Swelling can also cause activation of ion channels via indirect mechanisms including reduction of ionic strength. Therefore, cell swelling alone cannot be used as evidence of direct mechanosensitivity. New methods have been developed to apply mechanical force to specific locations of a cell, including the nerve terminals, or neurites, where mechanically activated ion channels are thought to be functioning (Poole et al., 2015Poole K. Moroni M. Lewin G.R. Sensory mechanotransduction at membrane-matrix interfaces.Pflugers Arch. 2015; 467: 121-132Crossref PubMed Scopus (0) Google Scholar). Poole et al. have developed an elastomeric pillar array where each pilus is controlled by a piezoelectric device and can be deflected to apply local mechanical indentation (Figure 2H). Using this system, the authors were able to show distinct populations of mechanically activated currents in dorsal root ganglia (DRG) neurons by substrate deflection at both the soma and the neurite (Poole et al., 2014Poole K. Herget R. Lapatsina L. Ngo H.D. Lewin G.R. Tuning Piezo ion channels to detect molecular-scale movements relevant for fine touch.Nat. Commun. 2014; 5: 3520Crossref PubMed Google Scholar). Along with studies of isolated cells, ex vivo preparations have also been used to study the function of mechanically activated somatosensory neurons. The primary advantage of this setup is the ability to keep intact the native organization of mechanoreceptors that innervate the skin. The skin-nerve preparation technique is used to record action potentials from the saphenous nerve upon mechanical indentation of the associated skin layer (Figure 2I) (Zimmermann et al., 2009Zimmermann K. Hein A. Hager U. Kaczmarek J.S. Turnquist B.P. Clapham D.E. Reeh P.W. Phenotyping sensory nerve endings in vitro in the mouse.Nat. Protoc. 2009; 4: 174-196Crossref PubMed Scopus (0) Google Scholar). A variation of this technique is to record directly from DRG neuron cell bodies instead of the saphenous nerve (Figure 2J) (Koerber and Woodbury, 2002Koerber H.R. Woodbury C.J. Comprehensive phenotyping of sensory neurons using an ex vivo somatosensory system.Physiol. Behav. 2002; 77: 589-594Crossref PubMed Scopus (33) Google Scholar, Li et al., 2011Li L. Rutlin M. Abraira V.E. Cassidy C. Kus L. Gong S. Jankowski M.P. Luo W. Heintz N. Koerber H.R. et al.The functional organization of cutaneous low-threshold mechanosensory neurons.Cell. 2011; 147: 1615-1627Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). Although distinct forms of mechanical force such as shear stress and membrane stretch are relevant to specific cell types, it is important to note that mechanically activated ion channels can often be activated by multiple types of physical forces. The commonality to all of the mechanical forces described above is the perturbation of the membrane lipid bilayer (Arnadóttir and Chalfie, 2010Arnadóttir J. Chalfie M. Eukaryotic mechanosensitive channels.Annu. Rev. Biophys. 2010; 39: 111-137Crossref PubMed Scopus (163) Google Scholar, Hoffman et al., 2011Hoffman B.D. Grashoff C. Schwartz M.A. Dynamic molecular processes mediate cellular mechanotransduction.Nature. 2011; 475: 316-323Crossref PubMed Scopus (398) Google Scholar, Kung, 2005Kung C. A possible unifying principle for mechanosensation.Nature. 2005; 436: 647-654Crossref PubMed Scopus (379) Google Scholar). Later in this review, we discuss the two leading proposed models for transmission of physical forces to mechanically activated ion channels. Sodium ion channels expressed in somatosensory neurons of C. elegans were among the first identified eukaryotic mechanically activated ion channels (Figure 3A) (Arnadóttir and Chalfie, 2010Arnadóttir J. Chalfie M. Eukaryotic mechanosensitive channels.Annu. Rev. Biophys. 2010; 39: 111-137Crossref PubMed Scopus (163) Google Scholar, Chalfie, 2009Chalfie M. Neurosensory mechanotransduction.Nat. Rev. Mol. Cell Biol. 2009; 10: 44-52Crossref PubMed Scopus (188) Google Scholar). The degenerin (deg) genes were so named because mutations that caused constitutively active sodium currents led to the degeneration of mechanosensitive neurons and rendered worms incapable of escaping from a physical poking stimulus (Chalfie and Sulston, 1981Chalfie M. Sulston J. Developmental genetics of the mechanosensory neurons of Caenorhabditis elegans.Dev. Biol. 1981; 82: 358-370Crossref PubMed Scopus (381) Google Scholar). Among the deg genes, MEC-4 and MEC-10 were shown to be pore-forming subunits of an ion channel complex required for the activity of the gentle touch receptor neurons ALM and PLM (O'Hagan et al., 2005O'Hagan R. Chalfie M. Goodman M.B. The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals.Nat. Neurosci. 2005; 8: 43-50Crossref PubMed Scopus (263) Google Scholar). Loss of MEC-4 or MEC-10 ablates the mechanosensitivity of PLM neurons in vivo, and missense mutations to MEC-10 alter the ion conductivity of these cells upon mechanical stimulation (O'Hagan et al., 2005O'Hagan R. Chalfie M. Goodman M.B. The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals.Nat. Neurosci. 2005; 8: 43-50Crossref PubMed Scopus (263) Google Scholar). However, neither MEC-4 nor MEC-10 is sufficient to confer mechanically activated currents in heterologous expression systems. When a constitutively active (degenerin) mutant form of MEC-4 or MEC-10 was expressed in Xenopus oocytes, an amiloride-sensitive sodium current was recorded, and the current amplitude was dramatically increased when these proteins were co-expressed with MEC-2, a stomatin-related integral membrane protein, and MEC-6, a paraoxonase-related integral membrane protein (Chelur et al., 2002Chelur D.S. Ernstrom G.G. Goodman M.B. Yao C.A. Chen L. O' Hagan R. Chalfie M. The mechanosensory protein MEC-6 is a subunit of the C. elegans touch-cell degenerin channel.Nature. 2002; 420: 669-673Crossref PubMed Scopus (108) Google Scholar, Goodman et al., 2002Goodman M.B. Ernstrom G.G. Chelur D.S. O'Hagan R. Yao C.A. Chalfie M. MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation.Nature. 2002; 415: 1039-1042Crossref PubMed Scopus (223) Google Scholar). Importantly, biochemical evidence for the existence of a multi-subunit complex has not yet been established. Two other DEG genes, degt-1 and deg-1, have been implicated as mechanotransducers in C. elegans. DEGT-1, along with MEC-10, are necessary for mechanically induced calcium transients in the nociceptive PVD neuron (Chatzigeorgiou et al., 2010Chatzigeorgiou M. Yoo S. Watson J.D. Lee W.H. Spencer W.C. Kindt K.S. Hwang S.W. Miller 3rd, D.M. Treinin M. Driscoll M. Schafer W.R. Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors.Nat. Neurosci. 2010; 13: 861-868Crossref PubMed Scopus (93) Google Scholar). DEGT-1 and MEC-10 co-localize in dendritic puncta of PVD neurons and loss of mec-10 in PVD neurons abolishes the escape response of worms to a physical poking stimulus. Whereas the PVD neurons sense noxious mechanical forces applied to the body of the worm, the ASH neuron is required for sensing nociceptive signals at the nose. In ASH neurons, DEG-1 is required for the majority (∼80%), but not entirety, of the mechanically induced currents (Geffeney et al., 2011Geffeney S.L. Cueva J.G. Glauser D.A. Doll J.C. Lee T.H. Montoya M. Karania S. Garakani A.M. Pruitt B.L. Goodman M.B. DEG/ENaC but not TRP channels are the major mechanoelectrical transduction channels in a C. elegans nociceptor.Neuron. 2011; 71: 845-857Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Mutations to the putative pore domain of DEG-1 alter the ion selectivity, arguing that DEG-1 is the pore-forming subunit of the mechanically activated channel in these cells. While deg genes have been well characterized in C. elegans, a role for the evolutionarily conserved orthologs in mechanotransduction in Drosophila or mammals is less clear. Two DEG/ENaC (Epithelial Sodium Channels) proteins, Pickpocket and Balboa, are necessary for mechanical activation of class IV dendritic arborization neurons in Drosophila larvae (Mauthner et al., 2014Mauthner S.E. Hwang R.Y. Lewis A.H. Xiao Q. Tsubouchi A. Wang Y. Honjo K. Skene J.H. Grandl J. Tracey Jr., W.D. Balboa binds to pickpocket in vivo and is required for mechanical nociception in Drosophila larvae.Curr. Biol. 2014; 24: 2920-2925Abstract Full Text Full Text PDF PubMed Google Scholar, Zhong et al., 2010Zhong L. Hwang R.Y. Tracey W.D. Pickpocket is a DEG/ENaC protein required for mechanical nociception in Drosophila larvae.Curr. Biol. 2010; 20: 429-434Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). However, similar to MEC-4 and MEC-10, neither gene is sufficient to generate mechanically induced currents in heterologous expression systems (Mauthner et al., 2014Mauthner S.E. Hwang R.Y. Lewis A.H. Xiao Q. Tsubouchi A. Wang Y. Honjo K. Skene J.H. Grandl J. Tracey Jr., W.D. Balboa binds to pickpocket in vivo and is required for mechanical nociception in Drosophila larvae.Curr. Biol. 2014; 24: 2920-2925Abstract Full Text Full Text PDF PubMed Google Scholar). In mammals, the evolutionarily related Acid Sensing Ion Channel genes (ASIC1-3) are expressed in DRG neurons but do not contribute to mechanosensitivity of these cells (Drew et al., 2004Drew L.J. Rohrer D.K. Price M.P. Blaver K.E. Cockayne D.A. Cesare P. Wood J.N. Acid-sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurones.J. Physiol. 2004; 556: 691-710Crossref PubMed Scopus (182) Google Scholar, Page et al., 2004Page A.J. Brierley S.M. Martin C.M. Martinez-Salgado C. Wemmie J.A. Brennan T.J. Symonds E. Omari T. Lewin G.R. Welsh M.J. Blackshaw L.A. The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function.Gastroenterology. 2004; 127: 1739-1747Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). ASIC genes are also expressed in nodose ganglia neurons that project to the aortic arch and the carotid sinus arteries and express mechanoreceptors that detect changes in blood pressure in a process termed the baroreceptor reflex (Lu et al., 2009Lu Y. Ma X. Sabharwal R. Snitsarev V. Morgan D. Rahmouni K. Drummond H.A. Whiteis C.A. Costa V. Price M. et al.The ion channel ASIC2 is required for baroreceptor and autonomic control of the circulation.Neuron. 2009; 64: 885-897Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). ASIC2−/− mice displayed elevated basal arterial pressure and heart rates, and showed signs of Dysautonomia, a broad term referring here to an impaired ability to regulate arterial function upon acute changes. Isolated nodose ganglia neurons from ASIC2−/− mice showed slightly decreased mechanically induced depolarization compared to wild-type controls, suggesting a role for ASIC2 in modulating the mechanosensitivity of these cells. Interestingly, the stomatin-like protein, STOML3 is evolutionarily related to MEC-2 and modulates the activity of mechanosensitive DRG neurons (Wetzel et al., 2007Wetzel C. Hu J. Riethmacher D. Benckendorff A. Harder L. Eilers A. Moshourab R. Kozlenkov A. Labuz D. Caspani O. et al.A stomatin-domain protein essential for touch sensation in the mouse.Nature. 2007; 445: 206-209Crossref PubMed Scopus (126) Google Scholar). Loss of Stoml3 increased the number of mechanically insensitive DRG nerve fibers and led to deficits in the ability of mice to sense a sandpaper-like textured surface. Stoml3 can modulate the sensitivity of both Piezo1 and Piezo2 in vitro by decreasing the mechanical threshold needed for activation of these channels (Poole et al., 2014Poole K. Herget R. Lapatsina L. Ngo H.D. Lewin G.R. Tuning Piezo ion channels to detect molecular-scale movements relevant for fine touch.Nat. Commun. 2014; 5: 3520Crossref PubMed Google Scholar). Transient receptor potential (TRP) ion channels are an evolutionarily conserved family of genes that are essential to a wide range of sensory functions (Dhaka et al., 2006Dhaka A. Viswanath V. Patapoutian A. Trp ion channels and temperature sensation.Annu. Rev. Neurosci. 2006; 29: 135-161Crossref PubMed Scopus (415) Google Scholar, Venkatachalam and Montell, 2007Venkatachalam K. Montell C. TRP channels.Annu. Rev. Biochem. 2007; 76: 387-417Crossref PubMed Scopus (950) Google Scholar). TRP channels can be generally classified into seven categories based on sequence homology: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV (Christensen and Corey, 2007Christensen A.P. Corey D.P. TRP channels in mechanosensation: direct or indirect activation?.Nat. Rev. Neurosci. 2007; 8: 510-521Crossref PubMed Scopus (251) Google Scholar). TRP channels are non-selective cation channels that associate as tetramers where each monomer contains six transmembrane (TM) domains and a pore loop domain between TM5 and TM6 (Figure 3B) (Cao et al., 2013Cao E. Liao M. Cheng Y. Julius D. TRPV1 structures in distinct conformations reveal activation mechanisms.Nature. 2013; 504: 113-118Crossref PubMed Scopus (311) Google Scholar, Liao et al., 2013Liao M. Cao E. Julius D. Cheng Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy.Nature. 2013; 504: 107-112Crossref PubMed Scopus (540) Google Scholar). TRP channels are polymodal in that they are activated by numerous stimuli including voltage, temperature, and small molecules and a number of TRP channel members have been implicated as candidate mechanotransducers in flies, worms, and mammals (Arnadóttir and Chalfie, 2010Arnadóttir J. Chalfie M. Eukaryotic mechanosensitive channels.Annu. Rev. Biophys. 2010; 39: 111-137Crossref PubMed Scopus (163) Google Scholar, Delmas and Coste, 2013Delmas P. Coste B. Mechano-gated ion channels in sensory systems.Cell. 2013; 155: 278-284Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). Research in invertebrate model organisms has elegantly demonstrated the function of TRP channels, and in particular TRPN orthologs, in touch and hearing. In Drosophila larvae, the TRPN ortholog, NOMPC, is expressed in Class III dendritic arborization neurons and is necessary for the response of larvae to light touch stimuli (Walker et al., 2000Walker R.G. Willingham A.T. Zuker C.S. A Drosophila mechanosensory transduction channel.Science. 2000; 287: 2229-2234Crossref PubMed Scopus (419) Google Scholar, Yan et al., 2013Yan Z. Zhang W. He Y. Gorczyca D. Xiang Y. Cheng L.E. Meltzer S. Jan L.Y. Jan Y.N. Drosophila NOMPC is a mechanotransduction channel subunit for gentle-touch sensation.Nature. 2013; 493: 221-225Crossref PubMed Scopus (112) Google Scholar). NOMPC is sufficient to confer mechanically activated currents when mis-expressed in class IV neurons and when heterologously expressed in the Drosophila S2 cell line. Furthermore, mutations in the putative pore domain alter the ion selectivity (Yan et al., 2013Yan Z. Zhang W. He Y. Gorczyca D. Xiang Y. Cheng L.E. Meltzer S. Jan L.Y. Jan Y.N. Drosophila NOMPC is a mechanotransduction channel subunit for gentle-touch sensation.Nature. 2013; 493: 221-225Crossref PubMed Scopus (112) Google Scholar). These qualities establish NOMPC as a mechanically activated ion channel required for Drosophila touch sensation. NOMPC also plays a critical role in auditory mechanotransduction in