CHEMICAL BIOLOGY

Mechanosensitive Channels

 

Boris Martinac, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia

doi: 10.1002/9780470048672.wecb306

 

Mechanosensitive (MS) channels function as molecular transducers of mechanical forces into electrical and/or chemical intracellular signals in living cells. These channels play a major role in the physiology of mechanosensory transduction encompassing cellular processes that range from regulation of cellular turgor and growth in microorganisms to touch, hearing, and blood pressure regulation in vertebrates. Together with the recent work on MS channels in eukaryotic cells studies of prokaryotic MS channels using a multidisciplinary approach based on the patch-clamp recording, X-ray crystallography, computer simulations, and electronparamagnetic resonance and fluorescence resonance energy transfer spectroscopy, have significantly contributed to our understanding of the relationship between the structure and function in these membrane proteins. In particular, experiments employing chemical manipulation of the physical properties of the membrane lipid bilayer have shed light on 1) how MS channels detect physical forces in cellular membranes, and 2) what causes structural conformational changes in MS channels in response to membrane tension.

 

Mechanosensitive (MS) channels are the main signaling molecules of mechanosensory transduction. They convert mechanical forces acting on cellular membranes into electrical and/or biochemical signals in various types of nonspecialized cells as well as specialized mechanoreceptor neurons (1). The patch-clamp technique, which allows electrophysiologists to study the activity of single-channel molecules, allowed the first recordings of MS channel currents in real time some 20 years ago (2). Although at some point MS channels were considered to be a possible patch-clamp recording artifact, our knowledge of their structure and function has grown to the point that nowadays these channels are central players in our understanding of protein-lipid bilayer interactions. The cloning of the bacterial MscL and MscS channels, the elucidation of their 3-D crystal structures (Fig. 1a and b), and the demonstration of their physiologic role in bacterial osmoregulation (3) have provided a basis for intensive research and rapid progress in studies of the structure and function in the MS class of ion channels. Furthermore, the cloning and genetic analysis of the mec genes in Cenorhabditis elegans (4), genetic and functional studies of the TRP-type MS channels (5), as well as molecular biologic and functional studies of the TREK-1 family of 2P-type potassium channels (6) have also contributed to our understanding of the role of MS channels in the physiology of mechanosensory transduction and in the pathology of several major human diseases (2). The major aim of this article is to summarize recent developments regarding MS channels, with a major focus on the physico-chemical principles that can account for the stretch sensitivity of these membrane proteins.

 

Biologic Background

Living cells are exposed to a variety of mechanical stimuli acting throughout the biosphere. The range of mechanical stimuli extends from thermal molecular agitation to potentially destructive cell swelling caused by osmotic pressure gradients. Since cellular membranes present a major target for mechanical stimuli, MS ion channels are the main signaling molecules designed to detect and translate these stimuli into biologically meaningful signals as illustrated by several examples given below:

1. In their natural environment, bacterial cells need to adapt to a wide range of osmotic conditions. Escherichia coli cells exposed to hypo-osmotic shock respond by a rapid release of cellular osmolytes such as proline, potassium glutamate, trehalose, and ATP. This ability prevents the cells from lysis by decreasing the turgor pressure on the challenge of a sudden shift in osmolarity. Bacterial MS channels, MscL and MscS (Fig. 1a and b), are major components of adaptation mechanisms to hypo-osmotic shock. Being located in the cytoplasmic membrane, MscL and MscS are activated by an increase of membrane tension caused by excessive water influx and small osmolytes are released in milliseconds. Large conductance and low ion selectivity allow these MS proteins to serve as “emergency valves” in preventing bacterial cell lysis (3).

2. Genetic screens of the nematode C. elegans have identified several membrane proteins being required for touch sensitivity of this worm. Four of these proteins, MEC-2, MEC-4, MEC-6, and MEC-10, form a mechanically gated ion channel complex (4). These proteins belong to a DEG/ENaC superfamily of amiloride-sensitive Na+ channels of the transporting epithelia with many of them suspected to be gated directly by mechanical stimuli. MEC-2, MEC-4, MEC-6, and MEC-10 proteins have been shown to underlay mechanoreceptor currents in this nematode. Consistent with the role of these channels in mechanotransduction in C. elegans is the finding that mutations in MEC-4 result in touch insensitivity, and dominant mutations in the same gene result in swelling-induced degeneration and lysis of the mechanosensory neurons.

3. TREK-1 channels belong to a superfamily of 2P-domain K+ channels. They are polymodal (i.e., gated by a variety of chemical and physical stimuli) K+ channels. They are opened by both physical (stretch, heat, voltage, cell swelling, and intracellular acidosis) and chemical stimuli (lysophospholipids, polyunsaturated fatty acids, membrane crenators, and volatile general anesthetics) (Fig. 2). Their main function is to maintain the resting level of membrane potential. Recent studies using TREK-1 knockout mice suggest a central role for TREK-1 in anesthesia, neuroprotection, pain reception, and depression (6).

4. TRPC1 is a member of the canonical TRP (transient receptor potential) subfamily of another large and diverse family of ion channels. TRP channels are expressed in many tissues in numerous organisms where they function as cellular sensors mediating responses to a variety of physical (e.g., light, osmolarity, temperature, and pH) and chemical stimuli (e.g., pheromones, odors, and nerve growth factor) (5). TRP channels function as specialized biologic sensors that are essential in processes such as hearing, vision, taste, and tactile sensation. Several TRP channels may be inherently mechanosensitive, including the TRPC1 channel, which has been identified as MscCa, the Ca2+ permeable MS channel in Xenopus oocytes (2).

 

 

Figure 1. Physical and chemical stimuli affecting the gating of bacterial MS channels. (A) The structure of the pentameric MscL channel (left) and a channel monomer (right) from Mycobacterium tuberculosis according to the 3-D structural model of a closed channel (7). MscL is activated by membrane stretch, amphipaths (e.g., lysophopholipids, chlorpromazine, and trinitrophenol) and parabens. The channel activity is inhibited by Gd3+and static magnetic fields (SMF) and is modulated by temperature and intracellular pH (3). (B) The structure of the MscS heptamer (left) and the channel monomer (right) from E. coli based on the 3-D structural model of MscS (8) most likely depicting an inactive or desensitized functional state of the channel (3). MscS is activated by membrane stretch, amphipaths, and parabens and is modulated by voltage. The activity of the channel is inhibited by Gd3+ and high hydrostatic pressure (HHP) (3). The arrows point at membrane structures (i.e., channel protein and/or lipid bilayer) affected by the specific stimuli.

 

Chemistry, structure, and gating mechanism

MS channels are composed of amino acids, which are the building blocks of all proteins. The number of amino acids varies largely between different types of MS channels. For example, a single monomer of the bacterial channel MscL of E. coli is made of 136 amino acids folded in several a-helices connected by loops. A short N-terminal a-helix of the MscL monomer is followed by two transmembrane helices TM1 and TM2 and a C-terminal cytoplasmic α-helical domain (Fig. 1a). The TM1 helix is connected to TM2 by a loop that extends into the pore region and lines the periplasmic side of the channel. A 3-D structure of MscL obtained by X-ray crystallography has revealed that the channel folds as a homopentamer (Fig. 1a) (7).

Diversity and heterogeneity of the MS class of channels is well illustrated by the fact that MscS, the second type of MS channels found in bacteria, differs significantly from MscL in its primary as well as quaternary structure. Each channel belongs to a separate subfamily of the large family of prokaryotic MS channels (3). A monomer of MscS is a small membrane protein of 286 amino acids. A 3-D crystal structure of MscS shows that the functional channel is a homoheptamer having a large, cytoplasmic region (Fig. 1b) (8). Each of the seven MscS subunits contains three transmembrane domains, TM1-TM3, with N-termini facing the periplasm and C-termini at the cytoplasmic end of the channel. According to the crystal structure, the TM3 helices line the channel pore, whereas the TM1 and TM2 helices constitute the sensors for membrane tension and voltage (3).

Eukaryotic MS channels are far more diverse than the prokaryotic MS channels suggesting that various types of MS channels known today may have become adapted independently and at several occasions during the evolution to specific tasks in mechanosensory transduction of living organisms. In other words, the evolution of MS channels likely converged from independent genetic origins toward a common function of transducing mechanical stimuli into meaningful biologic signals. For example, a monomer of the TREK-1 channel consists of 411 residues. Since its quaternary structure has not been determined experimentally, the functional channel is thought to be composed of two, most likely identical 2P-domains (6). Each 2P domain has four transmembrane segments, an extended extracellular loop, and intracellular N- and C-termini. Although structurally very different from MscL and MscS, the TREK-1 channel functionally closely resembles the bacterial channels. The modality of stimuli that affect its activity (Fig. 2) is very similar to the modality of stimuli affecting the activity of both bacterial channels (Fig. 1a and b). The mechanosensitivity of MscL, MscS, and TREK-1 have been well characterized (3, 6). Consequently, one would expect that a fundamental question on the extent to which the mechanism of gating by physical and chemical stimuli characteristic of prokaryotic (bacterial and archaeal) MS channels has been conserved and adapted to gating of MS channels in eukaryotes can be answered fairly by comparing mechanosensitive properties of the bacterial MS channels with TREK-1.

 

 

Figure 2. Polymodal activation of TREK-1 by physical and chemical stimuli. TREK-1 is opened by stretch, heat, intracellular acidosis, depolarization, lipids, and volatile general anesthetics, and it is closed by protein kinase A (PKA) and protein kinase C (PKC) phosphorylation pathways. TREK-1 is inhibited tonically by the actin cytoskeleton. The cytosolic carboxy C-terminal domain has a key role in the regulation of TREK1 activity. Phosphorylation of Ser333 by PKA and phosphorylation of both Ser333 and Ser300 by PKC in this region inhibit TREK-1 opening. cAMP, cyclic AMP; DG, diacylglycerol; pH,, internal pH (reproduced from Reference 6, with permission).

 

Currently two basic models describe gating of MS channels by mechanical force: the bilayer and the more speculative tethered model (1). A third model of indirect gating of MS channels by mechanical stimuli, which combines elements of the bilayer and tethered models and requires an intermediary mechanosensitive membrane protein to interact with an ion channel, has also been considered (2, 9). According to the bilayer model, the tension in the lipid bilayer alone is sufficient to gate directly the MS channels. This model was proposed initially for the gating of bacterial MS channels. To date, it has been documented in a large number of MS channels from both prokaryotic and eukaryotic organisms (Table 1) (10). Purified MscL, MscS, and other prokaryotic MS channels remain mechanosensitive when reconstituted into artificial liposomes (3). Several eukaryotic MS channels including 2P-type potassium channels TREK-1 and TRAAK, TRP-type channels TRPC1, as well as calcium-dependent stretch-activated potassium channels (SAKCa) have also been shown to be gated by the bilayer mechanism (Table 1) (10). In contrast, the tethered model invokes direct connections between MS channels and cytoskeletal proteins and/or extracellular matrix (ECM) and requires relative displacement of the channel gate with respect to the cytoskeleton or ECM for channel gating. Originally proposed for gating of MS channels in hair cells and chick skeletal muscle, this model should apply to eukaryotic MS channels in specialized mechanoreceptor cells (1, 10).

The evidence showing that lipids play an essential role in opening and closing not only of prokaryotic MS channels but also of the MS channels of fungi, plants, and animals has led recently to a proposal of a possible unifying principle for mechanosensation based on the bilayer mechanism (11). The main idea of the unifying principle is that forces from lipids gate MS channels independently of their evolutionary origin and type of cells in which they are found. According to this principle, tethering of MS channels to rigid elements (cytoskeleton or extracellular matrix) does not necessarily imply mechanical force transmission. Tethers could serve instead to station the channels close to the cell surface involved in mechanotransduc- tion and to attenuate or amplify the mechanical force and thus adjust the dynamic range within which MS channels operate in a particular cellular setting. The function of the cytoskeleton and/or extracellular matrix would thus consist in altering the forces within the lipid bilayer by absorbing mechanical stresses and modifying the time dependence of MS channel adaptation (1, 11).

 

Table 1. Summary of prokaryotic and eukaryotic MS channels identified at the molecular level

 

MS Channel

Source

Gating mechanism

Amphipaths

Physiological function

MscL

Bacteria

Bilayer

Yes

Cellular turgor Growth

MscS

Bacteria

Bilayer

Yes

Cellular turgor Growth

MscA1

Archaea

Bilayer

NT

Cellular turgor*

MscA2

Archaea

Bilayer

NT

Cellular turgor*

MscMJ

Archaea

Bilayer

Yes

Cellular turgor*

MscMJLR

Archaea

Bilayer

No

Cellular turgor*

MscTA

Archaea

Bilayer

Yes

Cellular turgor*

MEC4

C. elegans

Tether*

NT

Touch

TREK-1

Brain, heart

Bilayer

Yes

Resting membrane potential

TRAAK

Brain, spinal chord

Bilayer

Yes

Resting membrane potential

ENaC

Rat, human, C. elegans

Bilayer/tether*

Yes

Touch

TRPC1

Xenopus oocytes

Bilayer

NT

Unknown

TRPY

Fungi

Bilayer*

NT

Cellular turgor

TRPA1

Hair cells

Tether*

NT

Hearing

TRPN

Drosophila, zebrafish

Tether*

NT

Touch, Hearing

SAKCa

Chick heart

Bilayer/tether

Yes

Myogenic tone

Notes: The bacterial MS channels, MscL and MscS, are the only MS channel proteins whose 3-D structure has been determined. The gating mechanism and/or physiologic function of some MS channels have not been characterized fully. Note that in contrast to the bilayer mechanism, no single experimental result provides direct support for the tethered model of MS channel gating (1). NT indicates that the effect of amphipaths (CPZ and TNP) has not been tested in the particular type of MS channels (adopted from Reference 10, with permission).

*A likely gating mechanism or physiologic function that has not yet been established firmly.

 

Chemical Tools and Techniques

Several experimental techniques have proven extremely useful in studies of MS channels. Besides the already classic patch-clamp technique used for functional studies of ion channels, X-ray crystallography and recently spectroscopic techniques, including EPR (electronparamagnetic resonance) and FRET (fluorescence resonance energy transfer) spectroscopy, have helped to significantly advance our knowledge of the structure and molecular dynamics of MS channels (10). The method of reconstituting MS channels into artificial liposomes (3, 10) provided another major tool to advance our understanding of the basic physical and chemical principles underlying mechanosen- sitivity of MS channels (12). In regard to this method, it is important to remember that insertion of an MS protein into the bilayer of artificial liposomes requires energy because of hydrophobic mismatch between the protein and the bilayer, which results from the bilayer-protein interaction. The hydrophobic thickness of the bilayer adjacent to the membrane protein will tend to match the length of the protein’s hydrophobic exterior (Fig. 3) because any uncompensated mismatch will add a high energetic cost by exposing hydrophobic groups of amino acid residues to water. The energetic cost of transferring a hydrophobic protein surface from an organic solvent to an aqueous environment is approximately 17 mJm-2 (1). Hydrophobic matching can be achieved by stretching and/or tilting of the lipid chains, which are more flexible than relatively rigid proteins. Localized changes in bilayer thickness and curvature may also compensate for the mismatch (Fig. 3) (1). Consequently, bilayer dilation/thinning or changes in local membrane curvature could affect an MS-channel protein by shifting the equilibrium between the closed and the open channel conformations. This process has experimentally been demonstrated by reconstituting the MscL channel into phospholipid bilayers of different thickness and examining the channel function by the patch clamp as well as examining its structure by EPR spectroscopy. The experiments showed that although hydrophobic mismatch was not the driving force that could trigger the channel opening, the MscL reconstitution into thin bilayers (e.g., PC16, 16:1 dipalmitoleoylphosphatidylcholine) decreased the energy required to open the channel, whereas reconstitution into thick bilayers (e.g., PC20, 20:1 eicosenoyl-phosphatidylcholine) increased the energy (13). Consequently, although thinning the bilayer is not sufficient to fully open the channel, it contributes to decreasing the energy barrier that has to be overcome to open the channel.

The second possibility of gating MS channels by bilayer tension takes into consideration changes in intrinsic bilayer curvature as a possible trigger for the channel opening (Fig. 3). Experiments on bacterial MS channels suggested that a diverse group of substances with amphipathic or amphiphilic properties such as trinitrophenol (TNP), chlorpromazine (CPZ), local anesthetics, or lysophospholipids (LPC) could trigger gating in these MS channels in the absence of externally applied membrane tension (14). This finding was subsequently confirmed on several prokaryotic (3) and eukaryotic MS currents (10, 15-17). Experiments examining the effect of amphipaths on an MS channel structure and function by EPR spectroscopy and patch-clamp recording side by side were undertaken using again MscL as a model MS channel. Addition of LPC to one monolayer of liposomes reconstituted with MscL generated local stresses leading to redistribution of the transbilayer pressure profile in the lipid bilayer and causing the channels to open without applying membrane tension. These studies thus showed that by chemically modifying membrane lipid content, one could stabilize multiple conformational states in MS channels for a time sufficiently long for biophysical studies of membrane proteins. Furthermore, in contrast to hydrophobic mismatch, insertion of an amphipath into only one monolayer of the membrane bilayer is sufficient to activate fully an MS channel. Together, these findings support theoretical considerations, which suggested that variations in the lateral pressure within lipid bilayers of cell membranes could serve as a mechanism for modulation of protein function (18).

 

 

Figure 3. Possible mechanisms of MS channel activation by bilayer deformation forces. Hydrophobic mismatch and bilayer curvature are considered as deformation forces of pressure-induced changes in the lipid bilayer causing conformational changes in MS channels as indicated by the example of MscL (13). These changes were studied experimentally by reconstituting purified MscL proteins in liposome bilayers prepared from synthetic phosphatidylcholine lipids of well-defined composition. The changes in functional properties were examined by the patch-clamp technique, whereas the structural changes were determined by EPR and FRET spectroscopy. (Reproduced from Reference 12, with permission).

 

Practical Applications

The following examples illustrate the practical applications in nanotechnology and medicine that have resulted from the basic research on structure and function of MS channels:

1. A light-driven nanovalve was constructed using the MscL channel of E. coli as a template (19). The nanovalve is opened by long-wavelength ultraviolet radiation and can be closed by visible light. For this purpose, MscL was modified by attaching light-sensitive synthetic compounds that undergo light-induced charge separation causing reversible opening and closing of the channel. Such a light-driven nanovalve can, for example, be used in liposome-based drug delivery systems.

2. Bacterial MscL and MscS channels have been shown recently to have potential as selective targets for novel types of antibiotics (20). Namely, both channels are not only opened by amphipaths (3) but also by parabens, the alkyl esters of p-hydroxybenzoic acid, which seem to interact directly with the gate of the channels (20). The novel antibiotics based on parabens as lead compounds would, therefore, work as openers of MscL and MscS and thus compromise cellular turgor of bacterial cells, which inhibits cell growth and proliferation. In particular, MscL, identi- fled to date in many bacterial pathogens, seems to be an ideal target for the novel antibacterial agents because MscL is highly conserved in prokaryotic cells, but its homologues have not been found in animal and human cells (1). Consequently, an antibiotic targeting MscL could be broad-spectrum and selective, potentially targeting a range of pathogenic bacteria with expected minimal side effects to infected patients.

3. The growing number of human diseases, including cardiac arrhythmias, polycystic kidney disease, Duchenne muscular dystrophy, and tumorigenesis, to name a few, have been associated directly with changes in expression and/or gating of MS channels (2). The spider venom peptide GsMtx-4 was shown to reduce the extent of the abnormalities of the heartbeat induced by atrial flbrillation. Furthermore, GsMtx-4 also blocks MS channels in dystrophic muscle that helps to reduce muscle flber degeneration (2). These flndings are thus opening a possibility for treatment of both diseases.

 

Future Research Directions

A key issue that future studies on MS channels will continue to address is the question on unifying principles that could account for the mechanosensitivity of both prokaryotic and eukaryotic MS channels. As discussed in this article, the bilayer principle seems to apply to several channels from evolutionary diverse origins. Additional questions to address will be on the structural determinants critical for MS channel mechanosensitivity and on the nature of interactions between the channels and the membrane lipids. Finally, possible applications of these findings in nanotechnology and medicine will be central to the applied research that will result from the basic research on this fascinating class of membrane proteins.

 

Acknowledgment

I would like to thank G. R. Meyer for technical assistance.

 

References

1. Hamill OP, Martinac B. Molecular basis of mechanotransduction in living cells. Physiol. Rev. 2001; 81:685-740.

2. Hamill OP. Twenty odd years of stretch-sensitive channels. Pflugers Archiv 2006; 453:333-351.

3. Martinac B. 3.5 Billion years of mechanosensory transduction: structure and function of mechanosensitive channels in prokaryotes. Current Topics in Membranes, vol. 58. Owen P. Hamill, ed. 2007. Elsevier Inc., San Diego CA., pp. 25-57.

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5. Ramsey IS, Delling M, Clapham D. An introduction to TRP channels. Annu. Rev. Physiol. 2006; 68:619-647.

6. Honore E. The neuronal background K2P channels: focus on TREK-1. Nature Rev. 2007; 8:251-261.

7. Chang G, Spencer R, Lee A, Barclay M, Rees C. Structure of the MscL homologue from Mycobacterium tuberculosis: a gated mechanosensitive ion channel. Science 1998; 282:2220-2226.

8. Bass RB, Strop P, Barclay M, Rees D. Crystal structure of Escherichia coli MscS, a voltage-modulated and mechanosensitive channel. Science 2002; 298:1582-1587.

9. Lin S-Y, Corey DP. TRP channels in mechanosensation. Curr. Opin. Neurobiol. 2005; 15:350-357.

10. Martinac B. Mechanosensitive channels. In Biological Membrane Ion Channels: Dynamics, Structure, and Applications. Chung SH, Andersen OS, Krishnamurthy V, eds. 2007. Springer, New York. pp. 369-398.

11. Kung C. A possible unifying principle for mechanosensation. Nature 2005; 436:647-654.

12. Martinac B. Force from lipids: physical principles of gating mechanosensitive channels by mechanical force revealed by chemical manipulation of cellular membranes. Chem. Educat. 2005; 10:107-114.

13. Perozo E, Kloda A, Cortes DM, Martinac B. Physical principles underlying the transduction of bilayer deformation forces during mechano-sensitive channel gating. Nature Struct. Biol. 2002; 9:696-703.

14. Martinac B, Adler J, Kung C. Mechanosensitive ion channels of E. coli activated by amphipaths. Nature 1990; 348:261-263.

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16. Lin JH, Rydqvist B. The mechanotransduction of the crayfish stretch receptor neurone can be differentially activated or inactivated by local anaesthetics. Acta Physiol Scand. 1999; 166:65-74.

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19. Kocer A, Walko M, Meijberg W, Feringa BL. A light-actuated nanovalve derived from a channel protein. Science 2005; 309:755- 758.

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Further Reading

Corey DP. New TRP channels in hearing and mechanosensation. Neuron 2003; 39:585-588.

Corry B, Rigby P, Martinac B. Conformational changes involved in MscL channel gating measured using FRET spectroscopy. Biophys. J. 2005; 91:1032-1045.

Goodman MB, et al. MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation. Nature 2002; 415:1039-1042.

Hamill OP, Marty A, Neher E, Sackmann B, Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pfliigers Arch. Eur. J. Physiol. 1981; 391:85-100.

Maroto R, Raso A, Wood TG, Kurosky A, Martinac B, Hamill OP. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nature Cell Biol. 2005; 7:179-185.

Martinac B, Buechner M, Delcour AH, Adler J, Kung C. Pressure-sensitive ion channel in Escherichia coli. Proc. Natl. Acad. Sci. USA 1987; 84:2297-2301.

Martinac B, Kloda A. Evolutionary origins of mechanosensitive ion channels. Progress Biophys. Mol. Biol. 2003; 82:11-24.

Meyer GR, Gullingsrud J, Schulten K, Martinac B. Molecular dynamics study of MscL interactions with a curved lipid bilayer. Biophys. J. 2006; 91:1630-1637.

Owen P. Hamill, ed. Mechanosensitive Ion Channels, Current Topics in Membranes Part A, vol. 58. 2007. Elsevier Inc., New York. pp. 1-424.http://www.sciencedirect.com/science/bookseries/10635823. Owen P. Hamill, ed. Mechanosensitive Ion Channels, Current Topics in Membranes Part B, vol. 59. 2007. Elsevier Inc., New York. pp. 1-588.http://www.sciencedirect.com/science/bookseries/10635823. Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat. Neurosci. 1999; 2:422-426.

Perozo E, Cortes DM, Sompornpisut P. Kloda A, Martinac B. Structure of MscL in the open state and the molecular mechanism of gating in mechanosensitive channels. Nature 2002; 418:942-948a.

Perozo E, Rees DC. Structure and mechanism in prokaryotic mechano- sensitive channels. Curr. Opinion Struct. Biol. 2003; 13:432-442.

Steinbacher S, Bass R, Strop P, Rees DC. Mechanosensitive Channel of Large Conductance (MscL). 2007. http://www.rcsb.org/pdb/results/ results.do.

Steinbacher S, Bass R, Strop P, Rees DC. Mechanosensitive Channel of Small Conductance (MscS). 2007. http://www.rcsb.org/pdb/results/ results.do.

Sukharev SI, Corey D. Mechanosensitive channels: multiplicity of families and gating paradigms. Science’s STKE 2004, pp. 1-24. www.stke.org/cgi/content/ full/sigtrans; 2004/219/re4.

Voets T, Talavera K, Owsianik G, Nilius B. Sensing with TRP channels. Nature Chem. Biol. 2005; 1:85-92.

Yuan C, O’Connell RJ, Jacob RF, Mason RP, Treistman SN. Regulation of the gating of BKCa channel by lipid bilayer thickness. J. Biol. Chem. 2007; 282:7276-7286.

Zhou X-L, Batiza AF, Loukin SH, Palmer CP, Kung C, Saimi Y. The transient receptor potential channel on the yeast vacuole is mechanosensitive. Proc. Natl. Acad. Sci. U.S.A. 2003; 100:7105-7110.