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Origin of Mechanotransduction: Stretch-Activated Ion Channels

*.

* Corresponding Author: Departments of Physiology, Internal Medicine (Cardiology), and Biomedical Engineering, Medical College of Virginia, Virginia Commonwealth University, 1101 E. Marshall St., Richmond, Virginia 23298-0551, U.S.A. Email: clive.baumgarten@vcu.edu

Stretch-activated ion channels (SAC) serve as cardiac mechanotransducers. Mechanical stretch of intact tissue, isolated myocytes, or membrane patches rapidly elicits the open ing of poorly selective cation, K+, and Cl- SAC. Several voltage- and ligand-gated channels also are mechanosensitive. SAC alter cardiac electrical activity and, with prolonged stretch, cause an intracellular accumulation of Ca2+ and Na+ that can serve to trigger multiple signaling cascades and ultimately may contribute to remodeling of the heart in response to hemodynamic stress. This chapter reviews the transmission of mechanical forces, the biophysical characteristics of cardiac SAC, and how SAC activity may be coupled to signaling cascades and thereby initiates the complex response of the heart to stretch.

Introduction

Mechanical forces impinging on the heart play multiple roles in controlling cardiac function. 1,2 It is well-known that physiological mechanical stimuli, such as ventricular end diastole volumes, regulate the force of cardiac contraction and that atrial stretch regulates the secretion and production of atrial and brain natriuretic peptides. Transient mechanical stimuli alter cardiac electrical activity and rhythm, whereas sustained stimulation, for example, pressure or volume overload or wall motion abnormalities, activates a complex set of signaling cascades and gene programs leading to profound remodeling of the heart.

Cardiac responses to mechanical stimuli clearly are diverse. Yet, each process must begin with mechanotransduction, the conversion of mechanical force to electrical or biochemical signals that ultimately control cellular function. This chapter focuses on one instrument of the transduction process, stretch-activated channels (SAC).

SAC typically respond to mechanical perturbations within tens of milliseconds. Their activity is the initial response of the heart to stretch and can serve to trigger subsequent events. An overview of how SAC translate mechanical stimuli is presented in Figure 1. SAC alter cardiac function by two direct mechanisms. First, SAC directly affect electrical activity by virtue of the current they pass. This leads to alterations in action potential duration and shape, depolarization of the resting potential, and in some instances, stretch-induced automaticity.3 In turn, the altered action potential waveform and resting potential influence the behavior of virtually all voltage-dependent channels. The effects of stretch on cardiac electrical activity are called mechanoelectrical feedback.

Figure 1. Overview of mechanotransduction by stretch-activated channels (SAC).

Figure 1

Overview of mechanotransduction by stretch-activated channels (SAC). Mechanical forces are transmitted to SAC by extracellular matrix, integral membrane proteins, cytoskeleton, and perhaps, the membrane bilayer. The current carried by SAC has direct effects (more...)

Activation of SAC also directly leads to an ion influx that alters intracellular Ca2+ ([Ca2+]i) and Na+ ([Na+]i) concentrations,4 and elevation of [Na+]i favors additional cellular Ca2+ accumulation via Na+-Ca2+ exchange. Ca2+ acts as a signaling molecule to switch on Ca2+-dependent signaling cascades including PKC, PyK, calmodulin, CaM kinases, and phospholipases that modulate cardiac function by protein phosphorylation and ultimately by stimulating transcription factors and protein synthesis.5,6

Terminology

The term stretch-activated channel is adopted because it is widely used in the cardiac literature. More broadly, channels responding to mechanical forces should be termed mechanosensitive channels (MSC), which recognizes that channels can be activated or inactivated by stretch. Channels that respond to stretch, curvature, or deformation of the membrane are classified as mechanosensitive, even though the details of how a particular stimulus leads to altered channel function is rarely known. Osmotic or hydrostatic swelling or shrinkage of cells also regulate certain channels. Whereas these maneuvers stretch the membrane, it is unclear whether mechanical forces or another aspect of a volume change, such as dilution (or concentration) of cytoplasmic ions and macromolecules, is the stimulus. The term volume-sensitive channel will be used to differentiate between stimuli and, perhaps, underlying mechanisms. A distinction between mechano- and volume-sensitivity often has not been made in the literature, and this is a point of confusion. Cardiac volume-sensitive channels are reviewed elsewhere7-9 and will not be discussed in detail here. Finally, a number of voltage- and ligand-gated channels also are modulated by mechanical forces. This should not be surprising because most channels can be regulated by multiple mechanisms.

How Are Mechanical Forces Transmitted in Heart?

Forces that gate channels ultimately must be transmitted by the membrane bilayer, cytoskeleton, extracellular matrix, or a combination of these elements, as illustrated in Figure 2. Cardiac myocytes possess specialized structures for transmitting force from one myocyte to another and from the extracellular matrix (ECM) to the membrane and cytoskeleton.10,11 These structures also serve to organize and initiate signaling cascades.12-14 The membrane bilayer is supported by a tightly associated, submembrane (cortical) cytoskeleton that remains in place even after excision of a membrane patch. Collagenase-based myocyte isolation methods strip off components of the extracellular matrix, but laminin remains in a raster-like array on the sarcolemma and remnants of fibronectin are present.15 ECM also is present on cultured cardiac myocytes.16 As of yet, it is impossible to determine how each of these components influences the response of cardiac SAC to stretch. In contrast, cloned prokaryotic mechanosensitive channels can be functionally reconstituted in a protein-free lipid bilayer and are controlled by bilayer curvature, bilayer thickness, and the area occupied by the protein.17,18 This does not establish that force transmission through the bilayer is the only mechanism of activation in situ, however. Unc-105, a mechanosensitive C. elegans channel, binds to collagen IV and is thought to be activated by forces transmitted via ECM.19

Figure 2. Diagram of membrane bilayer and components of extracellular matrix (ECM) and cortical cytoskeleton that transmit mechanical forces in myocytes.

Figure 2

Diagram of membrane bilayer and components of extracellular matrix (ECM) and cortical cytoskeleton that transmit mechanical forces in myocytes. See figure for key. Hypothetical connections between SAC and both the ECM and cytoskeleton also are shown. (more...)

It is reasonable to think that the cytoskeleton plays a role SAC activation. A number of ion channels and transporters (e.g., Na+ channels, Na+-K+ pump, Na+- Ca2+ exchanger, Cl--HCO3- exchanger) and probably SAC are coupled to the cortical cytoskeleton by ankyrins, a family of peripheral membrane proteins.11,20 All three ankyrin genes (Ank1–3) are expressed in human heart and give rise to a multitude of protein isoforms by alternative splicing. Furthermore, a number of ion channels contain ankyrin-like binding domains.

At the level of the myocyte, force is transmitted at costameres, membrane specializations at the each Z-line and M-line that provide a physical link between the contractile apparatus and the cytoskeleton, membrane, and ECM.14,21 Costameres contain integrins, heterodimeric transmembrane proteins that are receptors for extracellular matrix proteins and connect to the cytoskeleton via talin, vinculin, and α-actinin. Integrins act as mechanotransducers22 and also act as signaling molecules, especially through focal adhesion kinase (FAK).23,24 A second system for linking ECM, membrane, and cytoskeleton is the dystrophin-dystroglycan complex (DGC).25 Dystroglycan is a transmembrane receptor for laminin and its cytoplasmic tail binds to costameric actin. Dystroglycan and the DGC form a strong mechanical link, and dystroglycans are important for organizing other components of the DGC, as well as for assembly of vinculin and spectrin into the costameres. Loss of DGC components and resulting sarcolemmal fragility underlies muscular dystrophies.26 Furthermore, gating of skeletal muscle SAC is altered in dystrophin-deficient mdx mice.27,28

In the intact heart, myocytes are coupled to each other by N-cadherins, transmembrane adhesion molecules that dimerize between cells. N-cadherins are found at the fascia adherens, which joins the actin cytoskeleton to the membrane, and at desmosomes, which attach intermediate filaments to the intercalated disc.11 This physical attachment between cells is disrupted during myocyte isolation, and the potential role of N-cadherins in cardiac mechanosensitivity has not been studied.

Characteristics of Mechanosensitive Currents in Single Channel Recordings

It has long been thought that specialized mechanosensory cells were likely to possess mechanosensitive ion channels as detectors, but the need for SAC in most other types of cells was not obvious. Wide-spread interest was kindled by the discovery that a poorly-selective cation channel is activated in skeletal muscle by stretching the sarcolemma when suction is applied to a patch pipette,29,30 as diagramed in Figure 3. With physiological Na+ and K+, the I-V relationship of the cation SAC in skeletal muscle is nearly linear, with a unitary conductance of 35 pS, and reverses at -30 mV; PK:PNa is 4 based on reversal potential (Erev) and 2 based on conductance.30 As negative pressure is increased from 0 to -50 mm Hg, thereby curving the sarcolemma outward and increasing tension on the membrane bilayer and adherent cortical cytoskeleton, cation SAC open probability increases ~4 orders of magnitude. Kinetic analysis of single channel open and closed times is consistent with a model with 3 closed and 1 open state. Stretch affects only a single rate constant, slowing the C1 → C2 transition moving away from the open state, which leads to increased open probability.29 Based on Eyring rate theory and the behavior of elastic materials, the high sensitivity of open probability to membrane tension suggests that the SAC gathers energy from a region 500 to >2000 Å in diameter.29,31 This is far too large an area to be occupied by the SAC itself and leads to the conclusion that the submembrane cytoskeleton must participate in mechanotransduction. Membrane lipid flows into patches held under negative pressure, and patch area and capacitance increase in parallel over time, and therefore, tension in the bilayer is not sustained.32

Figure 3. Unitary currents from cardiac SAC.

Figure 3

Unitary currents from cardiac SAC. A) Cation SAC recorded from on-cell patch on chick myocyte. (Modified from ref. 57 with permission from Lippincott Williams & Wilkins, http://www.lww.com.) B) K+ SAC from on-cell patch on rat atrial myocyte rapidly (more...)

Several types of cardiac SAC are found in cell-attached and excised patches from atrial and ventricular myocytes using the same pipette suction method. These include K+-selective, poorly selective cation, and anion SAC, and mechano-gated ATP-sensitive K+ channels (KATP), muscarinic K+ channels (KACh), and Ca2+-activated K+ channels (KCa) also have been identified. Examples of single channel records from cardiac SAC are shown in Figure 3,A–C. Kinetic analysis of cardiac SAC reveals a more complex picture than in skeletal muscle; depending on the channel, there can be multiple open and closed states, and the open times, closed times, or both are modulated by stretch.33-35

As fruitful as the pipette suction method has been, it remains uncertain whether the detailed properties of SAC in patches accurately reflect their properties in intact cells or tissues. Patch formation disrupts the connections between the cortical cytoskeleton and its more central members, which may modify the forces sensed by channels and their regulation by signaling molecules. Additionally, variable patch geometry complicates interpretations because it is likely that tension rather than applied pressure controls SAC activity. In addition, the effect of patch formation on caveolae is unknown. These specialized membrane lipid rafts are omega-shaped in cross-section, are estimated to comprise 20-30% of sarcolemmal area in atria,36 and are an important site of signaling integration.37 The shape of the caveolae and its association with cytoskeletal elements and integral membrane proteins suggest that caveolae might be responsive to imposed forces. Caveolae are osmotically responsive38 and appear to be incorporated into the membrane by increasing ventricular volume,39 although earlier quantitative studies in atria failed to detect stretch-induced unfolding of caveolae over a physiologic range of sarcomere lengths.36

K+ SAC

Cardiac K+ SAC were first reported in snail ventricular40,41 and also are present in embryonic chick ventricle33,35,42 and adult rat atrium43-45 and ventricle.46 Unitary conductance ranges from 25 to 200 pS, indicating multiple K+ SAC coexist, even in the same preparation.33,35 In chick heart, for example, the I-V relationships for 100 and 200 pS K+ SAC in cell-attached patches are linear with either K+ or Na+ in the pipette, i.e., with either a symmetrical or physiological ionic gradient.33 On the other hand, the dominant K+ SAC in rat heart has a conductance of ~100 pS in symmetrical K+, and the I-V relationship is outwardly rectifying with both a physiological and a symmetrical gradient.43-45

There is variability in the negative pressure required to maximally activate K+ SAC both between investigators and within a single study.43,44,46 This has been explained by arguing that tension in the bilayer or cortical cytoskeleton rather than the measured transmembrane pressure activates SAC.32 Variability then arises from differences in patch radius, which determines the relationship between pressure and tension by the Law of Laplace, and perhaps from the condition of the attached cytoskeleton.

The kinetics of the stretch response were studied by Niu and Sachs44 using a pressure clamp capable of changing pipette pressure in 2–4 ms. K+ SAC open with a latency of ~200 ms, and open probability undergoes adaptation with a time constant of ~1 s. Channels close within 50 ms on the release of negative pipette pressure, and spontaneous openings are suppressed for ~1 s. These data are consistent with the notion that force is coupled to the channel by a viscoelastic element, perhaps representing rearrangement of cytoskeletal elements over time, and that adaptation during continued negative pressure reflects a decrease in the force sensed by the channel. Alternatively, both the adaptation during suction and suppression of spontaneous events upon release can be modeled by including an inactivated state in the kinetic model of the channel. Transitions from the open to the inactivated state would reduce openings in the presences of a constant stimulus, and upon termination of the stimulus, fewer channels would initially return to the closed state and so basal activity would be suppressed.

Recent studies identified molecular candidates for K+ SAC: TREK-1, TREK-2 and TRAAK. These channels are members of the tandem two-pore domain (2P) K+ channel family (KCNK2, KCNK10, and KCNK4, respectively) that also includes TWIK, THIK and TALK (for review, see refs. 47-49). Unfortunately, none of the known mechanosensitive 2P K+ channel isoforms is detected in human heart,47,50 but TREK-1 is expressed in mouse heart51 and in rat atrial and ventricular myocytes.45,46 Heterologously expressed TREK-1 (KCNK2) opens in flickering bursts with a unitary conductance of ~100 pS in symmetrical K+, is reversibly opened by polyunsaturated fatty acids including arachidonate, and intracellular acidosis both activates the channel directly and sensitizes it to stretch.52 These properties mirror those of rat K+ SAC43-46 and support the argument that endogenous K+ SAC may be TREK-1.

Cation SAC

Pipette suction also activates multiple poorly selective cation SAC. These channels have been studied in neonatal and cultured rat ventricle,53,54 neonatal and adult rat atria,55,56 guinea pig ventricle,57 embryonic chick ventricle,33,42,57 and endocardial endothelial cells in porcine atria.58 As shown for K+ SAC, multiple cation SAC are present in the same preparation.33 Unitary conductances cluster around 21 to 25 pS, but 50 and 120 pS channels are also found. Based on electrophysiological data, cation SAC poorly distinguish between monovalent cations including Na+, K+, Cs+, Rb+, and Li+,33,55,56,58 and reported PK:PNa ratios vary from 0.7 to ~5. Divalent cations including Ca2+, Ba2+, and Mg2+ also are permeant.33,55,57 Conductance for Ca2+ was 80% of that of K+ with equimolar replacement55 and 40% with equal equivalents (i.e., 140 mM K+ vs. 70 mM Ca2+).58 Therefore, Na+ is the dominant charge carrier of inward cation SAC current with a physiological extracellular ionic milieu.

Cation SAC are fully activated by 20 — 30 mm Hg of suction,33 but another study reported full activation at 4 mm Hg.55 This difference may reflect methodological issues that affected tension.

Members of the TRP family of Ca2+-permeant cation channels are candidates for the cation SAC.59,60 In particular, TRPV4, a mammalian vanillinoid receptor-like TRP, is osmosensitive and is a homolog of C. elegans (OSM-9) and Drosophilia (NOMPC) channels that are osmoand mechanosensitive. TRPV4 is not expressed in heart, however.61

Pharmacology of K+ and Cation SAC

Yang and Sachs62 identified the lanthanide Gd3+ as a blocker of SAC in Xenopus oocytes, and this lanthanide also blocks most cardiac cation and K+ SAC at 10 — 30 μM.33,63 Gd3+ inhibits stretch-activated TRAAK,64 lysolipid-activated TREK-1,65 but not the background activity of TREK-1 even at 100 μM.51 Gd3+ has been widely adopted as a tool for identifying the physiological effects of SAC, but several cautions are in order. As noted in the original report, Gd3+ blocks multiple transport processes. In heart, nonspecific effects of Gd3+ include block of INa,66 ICa-L,54,67 IKr,68 and Na+-Ca2+ exchange.69 In addition, Gd3+ avidly binds to EGTA and physiologic anions such as phosphate and bicarbonate.70 These nonspecific and anion-binding properties complicate interpretation of experiments with Gd3+. Examples of Gd3+-insensitive cation55,56 and K+ SAC43 also have been reported. In two of these studies,43,55 EGTA apparently was included with Gd3+, and therefore, the free-Gd3+ concentration is likely to have been too low to be effective.70

Streptomycin and other cationic aminoglycoside antibiotics, such as neomycin and gentamicin, and amiloride and its derivatives block SAC in a variety of tissues (for review, see ref. 71). Streptomycin inhibits a poorly selective cardiac cation current and Ca2+ influx in response to stretch,72,73 but block of SAC by streptomycin apparently has not been studied at the single channel level in heart. Like Gd3+, streptomycin is nonspecific and blocks other ion channels including ICa-L, IKr, and IKs.74

Sachs and coworks discovered that the venom of a Chilian tarantula commonly called Grammastola spatulata (but reclassified as Phrixotrichus spatulatus75) blocks both a 21 pS cation SAC and a 90 pS K+ SAC in chick ventricular myocytes,42 as well as SAC and Ca2+ influx into GH3 cells upon hyposmotic swelling.76 An active peptide, GsMTx4, was purified by screening against an inwardly-rectifying cation SAC in patches on astrocytes, and GsMTx4 fully blocked a persistently-activated, cell volume-regulated, inwardly-rectifying cation SAC in ventricular myocytes from a rabbit aortic regurgitation heart failure model77 and stretch-induced atrial fibrillation in isolated rabbit hearts.78 GsMTx4 appears to be potent (blocks at 170 — 400 nM) and highly selective for SAC and is likely to be a useful tool for studying SAC-dependent processes in the future.

Cl- SAC

Volume-sensitive Cl- currents are well known in the heart,9 but the contribution of anions to stretch-activated currents often has been doubted. Nevertheless, Sato and Koumi34 described an 8.6 pS Cl- SAC in excised patches from human atrial myocytes. Activation occurs with positive pipette pressure in the outside-out and negative pressure in the inside-out configurations, and open probability increases from 0.03 at 4.5 mm Hg to 0.94 at 20 mm Hg. Unitary currents are blocked by 9-anthracene carboxylic acid (9AC) and DIDS with the same potency as the volume-sensitive whole-cell Cl- currents in these cells. An outwardly-rectifying mechanosensitive Cl- channel with a unitary conductance of 5–7 pS is described in C. elegans embryonic cells.79 This channel also fully activates with -20 mm Hg of pipette pressure and exhibits I- > Cl- permeability, as do volume-sensitive Cl- channels in heart.9 In contrast to volume-sensitive Cl- currents, C. elegans Cl- SAC undergo delayed rectification at positive voltages rather than inactivation.

Mechanosensitive Ligand-Gated Channels

Van Wagoner80 demonstrated that KATP channels in neonatal rat atrial myocytes are stimulated by negative pipette pressure in on-cell and excised patches. Open probability increase from ~0.01 to 0.7 at -27 mm Hg. This 52-pS channel was identified by its block by ATP and tolbutamide, a sulfonyl urea KATP inhibitor, and the potentiation of mechanosensitivity by pinacidil, a KATP channel opener, at concentrations too low to enhance basal channel activity. Stretch also reactivates KATP channels that have undergone rundown but does not overcome block by 5 mM ATP. Interestingly, ischemia potentiates mechanosensitivity of KATP channels.81

Muscarinic KACh channels in neonatal rat atria are modulated by membrane stretch, but only in the presence of ACh.82 Negative pressures up to -80 mm Hg with 10 μM ACh in the pipette increase open probability in a graded fashion by ~2-fold, a more modest stimulation than of other SAC. Although KACh is regulated by G protein, GK, several lines of evidence argue that the effects of stretch are independent of the ACh receptor and GK. Stretch of inside-out patches enhances channel activity after maximal activation of GK with GTPγS but does not alter sensitivity to GTP. In addition, stretch modulates KACh channels activated by trypsin via a G protein-independent pathway.

Kawakubo et al35 recently reported on a Gd3+-sensitive, 200 pS K+ SAC in embryonic chick ventricle that is similar to the 200 pS channel described previously.33 These authors concluded the channel is a Ca2+- activated K+ channel activated by ATP (KCa,ATP). As typical for Ca2+-activated K+ channels, charybdotoxin and TEA block KCa,ATP.

Characteristics of Mechanosensitive Currents in Whole-Cell Recordings

Applying a controlled, reproducible, and well-defined mechanical force to an isolated myocyte is technically challenging, and whether the methods adopted by investigators to stretch myocytes are physiologically relevant remains an open question. Given the geometry of the heart, the rotation of the alignment of myocytes going from endocardium to epicardium, and the varied mechanical disturbances introduced by cardiac pathologies, the force vectors impinging on myocytes in different situations are complex and not simple to reproduce experimentally on isolated myocytes. Moreover, because experimental tools are attached to myocytes by nonphysiological means, the transmission of applied forces and the response of the cell may or may not duplicate what transpires in situ.

Methods of Stretching Myocytes

Multiple techniques have been developed to apply force to cardiac myocytes (for references, see refs. 83,84), but only a subset of these have used to study mechanosensitive whole-cell currents, as illustrated in Figure 4. The effects of axial stretch of myocytes on whole-cell currents were first investigated by Sasaki et al85 by fixing one end of the cell to a polylysine-coated glass coverslip and the other end to a glass microtool (20 μm diam. ball) or suction pipette. By moving the tool or suction pipette with a micromanipulator, a controlled and measurable stretch was obtained. Axial stretch involving most of the myocyte also can be generated by stretching a cell between two patch56 or between functionalized concentric double pipettes86 or carbon filaments73,87,88 that adhere to the membrane because of their surface charge. Localized axial stretch between a microtool and a nearby patch pipette also has been examined.89,90 Typically, the entire myocyte or a selected region is stretched by 5 — 20%, as measured from the distance between the tools or from analysis of sarcomere length. Although these methods are designed to produce a uniform stretch, nonaxial force vectors are expected near the attachment points as forces are transmitted outward from the attachment point and towards the opposite face of the cell, and in some cases, a substantial fraction of the membrane is not stretched. Moreover, the membrane must adopt a cup-shape as it interacts with the curved glass tool or carbon fiber, and it is unclear how such membrane curvature complicates the nature of the applied stimulus.

Figure 4. Methods for stretching isolated myocyte whole recording whole-cell currents.

Figure 4

Methods for stretching isolated myocyte whole recording whole-cell currents. Sasaki et al stretched myocytes resting on agar (A) between two rounded (20 μm diam.) glass tools or (B) between a glass tool and a suction pipette (diam. 8 - 10 μm, (more...)

An alternative method for studying mechanosensitive whole-cell currents is to press down on the myocyte with a glass microtool42,91 or with the cantilever arm of an atomic-force microscope. 92 These maneuvers cause a localized and nonuniform stress by compressing the cell. As a depression forms at the site of contact, cytoplasm is displaced laterally, and the encompassing membrane is stretched. In a rod-shaped myocyte, the region of stretch would appear as a circumferential band. On the other hand, calculations indicate that pushing down on a rounded cultured chick myocyte by ~2–4 μm is sufficient to elicit a tension of 1–3 dyne/cm over most of the membrane bilayer and its attached cytoskeleton.42 A combination of compression in the Z-axis and motion in the plane of the membrane (X-Y plane) also has been examined.91 Another approach is to stretch myocytes with magnetic beads coated-with monoclonal antibodies to integral membrane proteins.93 This method applies force in an outward direction, along a line perpendicular to the sarcolemma. Finally, anionic and cationic amphiphiles that insert into the membrane have been used alter bilayer tension in cardiac myocytes,94 as well as in heterologous expression systems.48

Cation SAC

In view of the distinct methods of stimulation, one might expect widely varying results. To the contrary, a fundamental observation is remarkably consistent across atrial, ventricular, and sinoatrial node myocytes: stretch activates a current that typically reverses between ~0 and -15 mV and has a nearly linear I-V relationship, as shown in Figure 5. Similar currents are reported in ventricular myocytes from guinea pig,85,89 chick,42 rat,86,89 and mouse,95 rat atrium,56 rabbit sinoatrial node,88 as well as human atria and ventricle.89,90 In addition, a similar cation SAC currents are found in atrial and sinus nodal fibroblasts, and it is argued that fibroblast stretch affects cardiac electrical activity and heart rate (for review, see ref. 96).

Figure 5. Whole-cell stretch activated currents from rat ventricular myocyte.

Figure 5

Whole-cell stretch activated currents from rat ventricular myocyte. A) Myocytes were attached between pipettes coated with covalently linked positively charged groups and stretched ~ 4 μm (top trace). Current under control recordings with (more...)

As previously discussed for unitary SAC, whole-cell mechanosensitive currents are blocked by Gd3+,42,86,90 G. spatulata venom,42 and streptomycin.73,97 An exception to this pharmacology is a cation SAC in rat atrium that is reported to be Gd3+-insensitive.56 On the other hand, these authors found Gd3+ blocked a stretch-insensitive background cation current.

Ion substitution experiments and an Erev of ~0 to -15 mV establish that myocyte stretch activates a poorly selective cation current,42,56,90 and that Ca2+ also is permeant.89 It has been inferred from these data that only nonselective cation SAC are stimulated by whole-cell stretch. What happened to the K+ SAC found at the single channel level? Hu and Sachs42 argue that both a cation and K+ SAC are activated by myocyte stretch and that both contribute to the recorded current. This conclusion is based on their observation of 90 pS K+ SAC (Erev = -70 mV) and 21 pS cation SAC (Erev = -2 mV) unitary conductances that are turned on by pipette suction in the same preparation in which the whole-cell SAC Erev is -16 mV. If both cation and K+ SAC are activated by myocyte stretch, the intermediate Erev could be obtained. The exact value of Erev would reflect the relative number of K+ and cation SAC, their unitary conductances, and open probabilities. A test of this notion would be to selectively block either the K+ or cation SAC. This should shift Erev for the whole-cell current, but a selective blocker has not been identified. Another test would be to differentially activate the two types of SAC. Bett and Sachs92 reported in the same preparation that the cation SAC Erev is identical with a series of graded stimuli that elicit graded whole-cell currents. If both K+ and cation SAC are activated, as claimed,42 their sensitivity to stretch must be identical to obtain a constant Erev with graded activation,92 a surprising notion. Additional work is needed to clarify the role of K+ SAC in whole-cell currents.

Kinetics of the Whole-Cell Response

The time courses of activation and inactivation of mechanosensitive whole-cell currents were studied extensively by Sachs and colleagues.42,91,92 Activation generally appears to be rapid (in the range of 10–100 ms), although detailed activation kinetics were not reported. Currents follow a 1 Hz sinusoidal stimulus without an obvious phase shift.91 On the other hand, the response to applied stimulation can be complex. In some studies, the initially response is a spike of current lasting only ~10 ms, followed by a gradual increase in current over several seconds.91 Moreover, Bett and Sachs91 found that a stimulus that initially did not elicit a response generated a substantial response after 5 min of contact between the glass tool and the myocyte. Perhaps slow attachment of the membrane to the tool enhances transmission of force or activation of a signaling cascade is required to elicit the whole cell current.

Inactivation of whole cell SAC is noted in several preparations.42,85,91,92 In chick ventricular myocytes, Hu and Sachs42 described a rapid and substantial inactivation in 18% of cells. This was modeled as an O → I transition with a time constant of ~2 s. Myocytes seemed to recover in 10 — 15 s, but overall the current elicited by a second stretch 10 — 15 min latter was only ~75% of that by the initial stretch. Bett and Sachs92 found ~50% of the current inactivated and a faster decay of current using a different stimulus protocol. This behavior was modeled with series and parallel springs representing elasticity and a parallel dashpot representing viscosity. Whereas rearrangement of the cytoskeleton may reduce the force experienced by the channel over time, intracellular signaling and autocrine molecules also might contribute to current decay.

It should be noted that not all investigators have detected inactivation of whole-cell stretch-induced currents. For example, Kamkin et al89 applying local axial stretch concluded that the mechanosensitive current increases to a stable value within 200 ms and does not inactivate. The reason for this difference is unknown, but inactivation may depend on the characteristics of the stimulus.

Anion and Cation Currents with Integrin Stretch

To attempt to mimic the in situ situation, force can be applied specifically to molecules involved in physiologic force transmission. Browe and Baumgarten93 attached magnetic beads coated with β1 integrin monoclonal antibodies to rabbit ventricular myocytes. When a magnetic coil was activated, the beads and attached integrins were pulled upward and perpendicular to the long axis of the myocyte and membrane plane (fig. 4E). In solutions designed to isolate Cl- currents, integrin stretch activates an outwardly rectifying Cl- SAC that is blocked by tamoxifen, which also inhibits swelling-activated Cl- channels, and PP2, which blocks src and FAK protein tyrosine kinases.93 This Cl- SAC shares many of the properties of the volume-sensitive Cl- current, ICl,swell.9 In physiologic solutions, integrin stretch also activates a linear cation current that reverses near -10 mV. Thus integrin stretch can stimulate both anion and cation currents, whereas other forms of myocyte stretch appear to elicit only cation currents.63,97 Recent studies98 demonstrated that activation of Cl- SAC upon β1 integrin stretch depends on angiotensin II, AT1 receptors, and the upregulation of sarcolemmal NADPH oxidase. NADPH oxidase produces superoxide anions that are rapidly converted to H2O2 by superoxide dismutase. The stretch-induced activation of Cl- SAC is abrogated by losartan, an AT1 blocker, DPI and AEBSF, inhibitors of NADPH oxidase, and catalase, which degrades H2O2 to H2O. Moreover, exogenous H2O2 mimics the effect of stretch and activates a tamoxifen-sensitive outwardly rectifying Cl- current.

Although the magnetic bead method provides highly specific site of attachment via an antibody, the connection of integrin to the membrane and cytoskeleton and the interconnection of cytoskeletal proteins implies that forces will be distributed to multiple structural elements.99 Applied forces are small (typically 1 — 10 pN/bead), and the resulting stretch is localized and nonuniform. Magnetic beads also can be coated with ECM proteins, as previously done, for example, to examine stretch-induced Ca2+ fluxes in fibroblasts100 and other types of cells101 or with antibodies to other putative components of the mechanotransduction process.

Amphiphile-Induced Membrane Curvature

Another approach for studying SAC is to insert charged amphiphiles into the membrane. Amphiphilic molecules possess both charged hydrophilic and uncharged hydrophobic domains and, therefore, have detergent-like properties. Because of the natural asymmetric distribution of negatively charged phospholipids in the inner and outer leaflets of the membrane bilayer, cationic amphiphiles, such as chlorpromazine, accumulate in the inner leaflet, whereas anionic amphiphiles, such as trinitrophenol and arachidonate, accumulate in the outer leaflet.102 As a result, the tension in the bilayer is altered, and membrane curvature is induced (fig. 4F). Cationic amphiphiles mimic the curvature caused by cell shrinkage (cup-shape), and anionic molecules mimic the curvature caused by cell swelling (ball-shaped) or crenation, as occurs in erythrocytes. Mechanosensitive exogenously expressed TREK-1 channels are activated by anionic amphiphiles, and their activation is reversed by cationic amphiphiles, responses attributed to alteration of bilayer tension.48

Amphiphiles have multiple effects in cardiac preparations. Anionic and cation amphiphiles appropriately mimic cell swelling and shrinkage, respectively, in regulating volume-sensitive Cl- channels in canine ventricular myocytes in the absence of a volume change.94 Anionic amphiphiles enhance ICa-L but inhibit ICa-T in rabbit ventricular myocytes, whereas cationic amphiphiles have the opposite effects.103 Effects on Ca2+ currents were explain in terms of altered surface potential and altered lipid properties rather than as mechanosensitivity, however. Indeed, a plethora of cardiac membrane currents, transporters, and signaling cascades are modulated by amphiphiles, and the accumulation of certain amphiphiles during ischemia has been postulated as an important cause of arrhythmogenesis.104 Because amphiphiles are not specific, caution is necessary before ascribing their action solely to altered membrane tension and mechanosensitivity.

Voltage-and Ligand-Gated Channels

Data on the effects of whole cell stretch on voltage-gated ion channels is somewhat contradictory, perhaps reflecting the details of the stimulus or its duration.

IK1

Initial reports concluded that stretch did not alter IK1 in guinea-pig85 or chick105 ventricle. The response appears to depend on how the stimulus is delivered, however. Kamkin et al89 found the Cs+-sensitive difference current, IK1, is enhanced by local stretch of guinea pig ventricular myocytes, but edgewise compression of myocytes rotated with their thin edge up causes significant inhibition of IK1.97 Inhibition of IK1 also is elicited by stretching β1 integrins.93 Furthermore, the early study by Sasaki et al85 showed a rectification of SAC current negative to -70 mV that is consistent with inhibition of IK1, a possibility the authors briefly raised.

ICa-L

Initial reports also failed to identify consistent effects of stretch on ICa-L in guinea-pig, ferret, and rat ventricle.85,106,107 By contrast, a 15 — 25% depression of ICa-L is observed in guinea pig, rat, mouse, and human ventricle using localized stretch.89,90,95,97 Inhibition of ICa-L is prevented by dialysis with BAPTA, suggesting that Ca2+-dependent inactivation of ICa-L following stretch-induced Ca2+ influx was responsible.

Other Channels and Transporters

There are a few reports regarding other channels and transporters in heart. No effect on INa is detected in chick ventricle.105 Delayed rectifier K+ channels are stimulated, inhibited89,97 or unaffected,85 depending on how stretch is applied. Prolonged stretch activates the Na+-K+ pump (dihydrouabain-sensitive current), presumably due to elevation of [Na+]i.97 Because stretch-induced accumulation of [Ca2+]i and [Na+]i (see infra) has multiple effects on ion channels and transporters, both directly and via signaling cascades, it is likely that other effects will be identified in the future.

Effects of Stretch on Cardiac Electrical Activity

The overall effect of stretch on cardiac membrane currents is to produce an inward current at voltages negative to the plateau and an outward current at more positive potentials,42,85,89 as also is seen when imposing an action potential waveform as the voltage command.73 Such currents might be expected to depolarize resting potential and make the action potential more triangular, shortening action potential duration at 10 or 20% repolarization (e.g., APD10) but prolonging APD75 or APD90. The effect of the voltage trajectory on the activation and inactivation of voltage-dependent channels complicates predictions, however. Experimentally, stretch depolarizes the resting potential, decreases plateau amplitude, and either shortens APD or produces a crossover of the waveform as predicted above (for reviews, see refs. 3, 108, 109). The details of effects on APD depend, however, on the timing and duration of the stimulus and loading conditions. Nevertheless, the consistently observed abbreviation and negative shift of the plateau is expected to limit Ca2+ entry via both ICa-L and reverse mode Na+-Ca2+ exchange. Because of the complexity of interactions, computer simulations are necessary to fully unravel how SAC activation affects various voltage-dependent pathways and the accumulation of ions. Significant progress has been made taking this approach,88,109-113 and the consequences of nonuniform myocardial mechanics were considered recently.114 In a complementary approach, stretch-activated currents calculated in real-time were applied to unstretched myocytes by current clamp and elicited electrical responses characteristic of stretch.115

Stretch also modulates cardiac rhythm. This was first recognized nearly a century ago as the Bainbridge effect, wherein increased right atrial filling causes an acceleration of heart rate that usually is attributed to autonomic reflexes. A mechanism intrinsic to the heart also is needed, however, because stretch enhances diastolic depolarization and automaticity of Purkinje fibers and the sinoatrial node,116 and stretch-induced acceleration of pacemaker activity and depolarization of maximum diastolic potential are reproduced in isolated sinoatrial myocytes.88 Computer modeling indicates activation of a linear cation SAC is sufficient to explain these data.88

Besides enhancing normal automaticity, stretch can elicit ectopic beats, tachycardia, and fibrillation.3 Evidence for involvement of SAC in arrhythmias arising from brief stretch was first provided by Hansen et al,117 who demonstrated in isolated canine hearts that increasing left ventricular volume for 50 ms elicits ectopy that is blocked by 1–10 μM Gd3+ but not by Ca2+ channel blockers. Graded volume pulses produced graded depolarizations in monophasic action potential recordings that were Gd3+-sensitive and paralleled the propensity for arrhythmogenesis.118 Gd3+ also blocks delayed afterdepolarizations in atria,119 inhibits atrial fibrillation,120 and minimizes dispersion of ventricular repolarization121 during pressure overload. Because of the multiple effects of Gd3+, a clearer case can be made with GsMTx4, the selective cation SAC blocker purified from tarantula venom.77 GsMTx4 suppresses both atrial fibrillation induced by elevated intra-atrial pressure78 and spontaneous depolarizations and runs of tachycardia in ventricular myocytes isolated from an aortic regurgitation model of heart failure.122

Stretch-Induced Elevation of [Ca2+]i and [Na+]i

As discussed previously, electrophysiologic data indicate that cation SAC are permeant to Na+ and Ca2+ and that Na+ is the dominant inward charge carrier under physiologic conditions. This leads to the notion that activation of cation SAC will increase [Na+]i and [Ca2+]i, and significant experimental support has been garnered for this idea. SAC do not act in isolation, however, and other transport processes including Na+-Ca2+ and Na+-H+ exchange, Na+-K+ pump, ICa-L, sarcoplasmic reticulum (SR), and Ca2+ binding to troponin-c directly and indirectly contribute to the response to stretch (for review, see ref. 123).

A stretch-induced slow increase in Ca2+ transients over a number of minutes was first documented in intact cat papillary muscle and trabeculae based on aequorin bioluminescence.124 Stretch also increases diastolic [Ca2+]i measured with indo-1125 or fura-2106 in isolated guinea pig ventricular myocytes, and Ca2+ transients but not [Ca2+]i in rat ventricular myocytes.107 In a more intact model, Tavi et al111,126 examined the response of rat left atrial appendage to physiological increases in intra-atrial pressure, 1 — 4 mm Hg, using indo-1. As shown for isolated rat myocytes, stretch increases Ca2+ transients.111,126 In addition, diastolic [Ca2+]i increases when the cytosol is made slightly acidotic (0.18 pH units).126 Thus, a convincing case is made for stretch-induced Ca2+ uptake, but the source of Ca2+ is not defined by these studies.

Sigurdson et al4 provided the first evidence for the involvement of SAC in stretch-induced Ca2+ uptake. On prodding fluo-3-loaded chick ventricular cells with a glass tool, they elicited localized Ca2+ influx that often induced waves of Ca2+-induced Ca2+ release that spread throughout the myocyte. They also saw a diffuse increase in [Ca2+]i by pulling on a neighboring attached myocyte. Importantly, they found that stretch-induced Ca2+ influx was blocked by 20 μM Gd3+, suggesting SAC are involved, or by removing extracellular Ca2+. Another SAC blocker, streptomycin (40 μM), prevents and reverses the large stretch-induced increase in [Ca2+]i (up to 60% of the Ca2+ transient) on axial stretch of guinea pig myocytes72,73 without altering ICa-L,72 or APD and contractility in unstretched myocytes.73 Supporting the role of SAC, suppression of SR function with ryanodine and INa with tetrodotoxin has no effect; the Ca2+ channel blocker verapamil reduces stretch-induced Ca2+ entry by ~25% in unclamped myocytes, although this probably is due to altered action potential shape.110 Ca2+ entry upon bidirectional stretch of neonatal rat myocytes cultured on laminin-127 or collagen-coated128 silicon rubber sheets is fully or 50% blocked by Gd3+. Neither ryanodine127 nor a combination or ruthenium red and procaine128 suppress the rise in Ca2+ in this model. On the other hand, Ruwhof et al128 found that diltiazem (100 μM) is almost as effective as Gd3+ in blocking the elevation of [Ca2+]i with bidirectional stretch and fully blocks the response to prodding cells. Stretch failed to increase diastolic [Ca2+]i in isolated adult rat ventricular myocytes107 and trabeculae.129 In fact a small decrease in diastolic [Ca2+]i in rat ventricular trabeculae was reported by Alvarez et al,130 although these authors simultaneously observed an increase in the Ca2+ transient.

Because Na+ is the predominant charge carrier for inward cation SAC current, increased [Na+]i also might be expected upon stretch. Such an increase in [Na+]i is observed in rat ventricular trabeculae130 and cat papillary muscle131 but not in isolated rat ventricular myocytes,107 as measured with the ratiometric fluorophore SBFI. A localized subsarcolemmal increase in [Na+]i is described in isolated mouse ventricular myocytes by Isenberg et al,97 who used the indicator sodium green with a pseudoratiometric method and simultaneously defined the sarcolemma by ANEPPS fluorescence. After a 4-min stretch, subsarcolemmal hot spots are noted; the most common pixel value in the hot spots corresponded to an increase of [Na+]i from 11 to 24 mM, and 28% of the pixels gave values between 25 and 50 mM. An increase in cytoplasmic Na+ content was confirmed by electron probe analysis,97 which reports the sum of free and bound Na+ (as much as 75% of cytoplasmic Na+ is bound). Na+ content increases 2.26-fold in the peripheral cytoplasm and 1.88-fold in the center of the cell after a 2-min stretch. Such large increases in [Na+]i are a powerful stimulant for reverse mode Na+-Ca2+ exchange, which mediates Ca2+ influx.

Although it is appealing to attribute these increases in Na+ to Na+ permeant cation SAC, direct evidence for the involvement of SAC has not been presented, and alternative mechanisms must be considered. Stretch evokes important autocrine/paracrine signaling cascades in heart. Stored angiotensin is rapidly released from myocytes132 and, via AT1 receptors, causes the secretion of endothelin-1.133 In turn, binding of endothelin-1 to cardiac ETA receptors activates the Na+-H+ exchanger (NHE1) by means of PKC, ERK1/2 and p90-RS kinase.134,135 Stretch-induced stimulation of Na+-H+ exchange plays an important role in elevation of [Na+]i and [Ca2+]i in rat trabeculae130 and cat papillary muscle,131 and Na+ accumulation is abrogated by AT1 and ETA receptor blockers. Na+ entry via Na+-H+ exchange causes reverse mode Na+-Ca2+ exchange that ultimately is dependent on activation of both ETA131 and AT1136 receptors.

Conclusion

The transduction of mechanical forces by SAC rapidly results in altered cardiac electrical activity and the influx of Ca2+ and Na+. The accumulation of these ions contributes to altered contractile performance and may serve to initiate a variety of Ca2+-dependent signaling cascades that regulate cardiac function via protein phosphorylation and ultimately gene expression. It is equally clear, however, that SAC are not the only mechanism for transducing mechanical stresses that impinge on the heart and that these signaling processes overlap. While the role of SAC in mechanoelectrical feedback is well established, much work and better tools will be needed to definitively identify the contribution of SAC to the initiation of signaling cascades.

Acknowledgments

Supported by grants from the National Institutes of Health (HL-26764, HL-65435) and the American Heart Association.

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