Mechanosensitive channels (MSCs), mechanosensitive ion channels or stretch-gated ion channels are membrane proteins capable of responding to mechanical stress over a wide dynamic range of external mechanical stimuli. They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They are the sensors for a number of systems including the senses of touch, hearing and balance, as well as participating in cardiovascular regulation and osmotic homeostasis (e.g. thirst). The channels vary in selectivity for the permeating ions from nonselective between anions and cations in bacteria, to cation selective allowing passage Ca2+, K+ and Na+ in eukaryotes, and highly selective K+ channels in bacteria and eukaryotes.
All organisms, and apparently all cell types, sense and respond to mechanical stimuli. MSCs function as mechanotransducers capable of generating both electrical and ion flux signals as a response to external or internal stimuli. Under extreme turgor in bacteria, non selective MSCs such as MSCL and MSCS serve as safety valves to prevent lysis. In specialized cells of the higher organisms, other types of MSCs are probably the basis of the senses of hearing and touch and sense the stress needed for muscular coordination. However, none of these channels have been cloned. MSCs also allow plants to distinguish up from down by sensing the force of gravity. MSCs are not pressure-sensitive, but sensitive to local stress, most likely tension in the surrounding lipid bilayer.
History
Mechanosensitive channels were discovered in 1983 in the skeletal muscle of embryonic chicks by Falguni Guharay and Frederick Sachs. They were also observed (pub. 1986) in Xenopus oocytes, and frequently studied since that time. Since then, MSCs have been found in cells from bacteria to humans: they are now known to be present in all three domains of life (Archaea, Bacteria and Eukarya, incl. plants and fungi). In the decades since the discovery of MS, the understanding of their structure and function has increased greatly, and several have been cloned. Specifically, the cloned eukaryotic mechanosensitive channels include the K+ selective 2P domain channelsPeyronnet, R. et al. Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels. Cell Reports 1 (in press), 241-250 (2012)Chemin, J. et al. in Mechanosensitive Ion Channels, Pt B Vol. 59 Current Topics in Membranes (ed O.P. Hamill) Ch. 7, 155-170 (Academic Press, 2007).>Honore, E., Patel, A. A., Kohl, P., Franz, M. R. & Sachs, F. in Cardiac Mechano-Electric Feedback and Arrhythmias: From Pipette to Patient (Elsevier 2004) and the recently cloned cation selective PIEZO family (PIEZO1 and PIEZO2).
Classification
MSCs can be classified based on the type of ion to which they are permeable:
Cation Selective MSCs: As the name suggests, they exhibit a selective permeability for positive ions with the most selective channels being those for K+. The most common eukaryotic MSCs are cation selective passing Na+, K+ and Ca2+ but not Mg2+. They have a single channel conductance range (25-35 pS) and they are blocked by trivalent ion Gadolinium. The K+ selective MSCs such as TREK-1 are not blocked by Gd3+. Anion Channels: they exhibit a significant permeability for negative ions, and are not predominant as cation MS. They have a large conductance range (> 300pS). Non Selective ion channels: As the name indicates, they do not differentiate between positive and negative channels those are more common to Archaea and Bacteria, but rarely found in Eukarya.
Broadly, most MSCs can be classified as lipid-gated channels.
Functions For a protein to be considered mechanosensitive, it must respond to a mechanical deformation of the membrane. Mechanical deformations can include changes in the tension, thickness, or curvature of the membrane. Mechanosensitive channels respond to membrane tension by altering their conformation between an open state and a closed state. One type of mechanically sensitive ion channel activates specialized sensory cells, such as cochlear hair cells and some touch sensory neurons, in response to forces applied to proteins.
Stretch-activated ion channels are required for the initial formation of an action potential from a mechanical stimulus, for example by the mechanoreceptors in vibrissae (whiskers) of some animals such as rodents.
Afferent nerve fibers responsible for sensory stimulus detection and feedback are especially sensitive to stimulation. This results from the specialized mechanoreceptor cells that are superimposed upon the afferent nerve fibers. Stretch-activated ion channels are located on these mechanoreceptor cells and serve to lower the action potential threshold, thus making the afferent nerves more sensitive to stimulation. Afferent nerve endings without mechanoreceptor cells are called free nerve endings. They are less sensitive than the encapsulated afferent fibers and generally function in the perception of pain.
Stretch-activated ion channels are responsible for many bodily functions in mammals. In the skin they are responsible for sensing vibration, pressure sensation, stretch, touch, and light touch. They are expressed in sensory modalities including taste, hearing, smell, heat sensation, volume control, and vision. They can also regulate internal functions of our body including, but not limited to, osmotic pressure in cells, blood pressure in veins and arteries, micturition, and heart electrophysiology and contractility. In addition to these functionalities, stretch-activated ion channels have also been found to be involved with balance and proprioceptive sensation.
Channels that have traditionally been known as just "voltage-" or "ligand-gated" have also been found to be mechanically sensitive as well. Channels exhibit mechanical sensitivity as a general property. However, mechanical stress affects various types of channels in different ways. Voltage and ligand gated channels can be modified slightly by mechanical stimulation, which might change their responsiveness or permeability slightly, but they still respond primarily to voltage or ligands, respectively.
Examples The different families of stretch-activated ion channels are responsible for different functions around the body. The DEG/ENaC family consists of two subgroups: the ENaC subfamily regulates Na+ reabsorption in kidney and lung epithelia; the ASIC subfamily is involved in fear conditioning, memory formation, and pain sensation. The TRP superfamily of channels are found in sensory receptor cells that are involved in heat sensation, taste, smell, touch, and osmotic and volume regulation. MscM, MscS, and MscL channels (mechanosensitive channels of mini, small, and large conductance) regulate osmotic pressure in cells by releasing intracellular fluid when they become too stretched. In the body, a possible role in myoblast development has been described. Furthermore, mechanically gated ion channels are also found in the stereocilia of the inner ear. Sound waves are able to bend the stereocilia and open up ion channels leading to the creation of nerve impulses. These channels also play a role in sensing vibration and pressure via activation of Pacinian corpuscles in the skin.
Transduction mechanisms There are two different types of stretch-activated channels between which it is important to distinguish: mechanically gated channels, which are directly influenced by mechanical deformations of the membrane, and mechanically sensitive channels, which are opened by second messengers released from the true mechanically gated channel.
Mechanical deformations in the cell membrane can increase the probability of the channels opening. Proteins of the extracellular matrix and cytoskeleton are tethered to extra - and intra-cytoplasmic domains, respectively, of the stretch-activated ion channels. Tension on these mechanosensory proteins causes these proteins to act as a signaling intermediate, resulting in the opening of the ion channel. All known stretch-activated ion channels in prokaryotic cells have been found to be opened by direct deformation of the lipid bilayer membrane. Channels that have been shown to exclusively use this mechanism of gating are the TREK-1 and TRAAK channels. In studies using mammalian hair cells, the mechanism that pulls on proteins tethered from the intra- and extra-cytoplasmic domain of the channel to the cytoskeleton and extracellular matrix, respectively, is the most likely model for ion channel opening.
Mechanical deformation of the cell membrane can be achieved by a number of experimental interventions, including magnetic actuation of nanoparticles. An example of this is the control of calcium influx of axons and boutons within neural networks.. Note that this is not an indication of 'magnetic stimulation' of mechanosensitive channels.
Gating mechanism
Although MS vary in many aspects, structures and functions, all the MS studied to date share an important feature: in a process called gating, they all open in a pore-like manner when protein channels are activated by a mechanical stimulus. There are currently two models of the gating process that explain how membrane-activated ion channels open.
Lipid bilayer Tension or stretch model: In this model tension in the lipid bilayer triggers conformational changes, thus leading to the opening of the channels. The tension perceived by the protein comes from the lipids. It has been demonstrated that the tension/stretch profile in the lipid bilayer is originated by membrane curvature and bilayer-protein hydrophobic mismatch.
Spring-like Tether model: In this model a spring-like tether is attached directly to the MS channel and can be present in either the cytoskeleton or the extracellular matrix linking these elements together. When external stimuli deflect the tether the displacement opens the channel. This particular mechanism has been demonstrated to be the responsible for gating hair cells which are responsible for hearing in vertebrates.
Bacterial MSCs
Bacterial MS channels were first discovered by patch-clamp experiments in E. coli. They have been classified based on their conductance as mini (MscM), small (MscS) and large large (MscL)). These channels function in tandem-mode and are responsible of turgor regulation in bacteria; when activated by changes in the osmotic pressure. MscM is activated first at really low pressures followed by MscS, and finally MscL being the last chance of survival during osmotic shock. Their task was demonstrated when bacteria missing both MscS and MscL were lysed after exposure to osmotic downshocks.
MscS: Small conductance mechanosensitive channel.
The main conductance is 1nS in buffer solution. Channel-proteins have been found in gram-positive and gram-negative bacteria, archaea and plants. MscS channel was found after studies in E. coli spheroplasts. The identification of the gene family necessitated for MS of small conductance was as two different channels. YggB encoding MscS and KefA encoding MscK in E. coli further confirm its role osmotic regulation. Mutagenesis studies showed that when both genes YggB and KefA were deleted MscS lost its function, but maintain MscL and MscM, but mutants deficient of YggB and MscL showed that the function of those channel is to open in respond to pressure range right before cell rupture.