Mechanically Gated Channels and their Regulation

Mechanosensitivity in Cells and Tissues

Volume 6

Series Editors

A. KamkinDepartment of Fundamental and Applied Physiology, Russian State MedicalUniversity, Ostrovitjanova Str. 1, 117997 Moscow, Russia

I. LozinskyDepartment of Fundamental and Applied Physiology, Russian State MedicalUniversity, Ostrovitjanova Str.1, 117997 Moscow, Russia

First Editors of the Series

I. Kiseleva: 2008–2012

For further volumes:http://www.springer.com/series/7878

Andre Kamkin • Ilya LozinskyEditors

Mechanically Gated Channelsand their Regulation

Foreword by Maik Gollasch

2123

EditorsAndre Kamkin Ilya LozinskyDepartment of Fundamental Department of Fundamentaland Applied Physiology and Applied PhysiologyRussian State Medical University Russian State Medical UniversityMoscow MoscowRussia Russia

Editorial AssistantNatalia E. LapinaDivision of Neurosurgical ResearchMedical Faculty MannheimRuprecht Karls-University HeidelbergMannheimGermany

ISBN 978-94-007-5072-2 ISBN 978-94-007-5073-9 (eBook)DOI 10.1007/978-94-007-5073-9Springer Dordrecht Heidelberg London New York

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Foreword

Research on mechanosensation and mechanotransduction is a challenge for allclinician-scientists, in part because of the complexities of the relevant basic sci-ence, and because it is crucial for maintaining life and is observed on many levelsof the organism. In recent years, few fields have changed so dramatically as those inbiology of mechanosensationa and mechanotransduction. The main areas of progressinvolve molecular identification of candidates within large and different families ofion channels, identification of their interacting molecules, validation by methods ofmolecular biology, cell biology and electrophysiology, and identification of biologi-cal and cellular systems in vivo. The application of these methods has made all stepsof discoveries not only faster, but also more precise. It is common for medical stu-dents, staff at all levels of training, researchers in the field to feel some apprehensionabout tackling these challenges, and clear overviews in this field are highly valued.

Hence, it is mandatory for those of us involved in research and teaching ofmechanobiology to keep pace with the continuous progress in this field, by receivingthe experts’ overview, as presented in this book.

In this context, the current book will fill a real need. Andre Kamkin andIlya Lozinsky have drawn together an international expert team of expert scien-tist in mechanobiology and ion channels and tasked them to bring an overview in15 chapters about recent discoveries in this emerging field of research.

I congratulate the editors and all contributors for their in-deep view into thisin this rapidly growing field, for their consistent and disciplined use of an easyunderstanding format, and strongly recommend the book to all those who wish todeepen their understanding of the role of mechanobiology and ion channels in healthand diseases, in the interest of better care for our patients.

Berlin, Germany Maik Gollasch, MD PhDProfessor of Medicine

Charité University Medicine

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Editorial

Mechanically Gated Channels

Andre Kamkin and Ilia Lozinsky

Cell reaction to mechanical stress is the oldest type of reaction from the point ofview of evolution. Therefore response to mechanical stress is typical for all organ-isms, from bacteria to mammals. R. Kaufmann and U. Theophile (a.k.a. Ravens)in 1967 and M. J. Lab in 1968 were the first to suggest that mechanical changes inheart during contraction or other mechanical stress modulate its electric activity. In1986 A. Kamkin and I. Kiseleva for the first time reported existence of mechani-cally induced potentials in cardiac fibroblasts (Kamkin et al. 1986, 1988; Kiselevaet al. 1987). Now it is known that mechanical stress of the cell triggers electro-physiological and biochemical responses in cells. Mechanical stress can influencephysiological processes at the molecular, cellular, and systemic level. During last30 years of investigation of cellular membrane responses to mechanical stress therewas a major progress in both phenomenological description of the ongoing processesand investigation of the cellular response mechanisms to mechanical stress. It wasshown than one of the mechanisms via which the cell responds to mechanical stressis mediated by ion channels reacting to membrane tension. Such channels were origi-nally called mechanosensitive channels (MSCs: Guharay and Sachs 1984), and wereredefined as mechanically gated channels (MGCs: Kirber et al. 1990) in the samemanner as it was done with voltage and ligand gated channels. MGCs, reacting tothe membrane tension, were shown to play the key role in one of the mechanisms,through which the cell responds to mechanical stimulus. Sachs and Morris (1998)noted that MGCs are channels that recognize mechanical deformation as a properphysiological signal and react to mechanical stimulation with changes in kinetics.MSCs, as a term, is now days usually used to describe channels that only modulatetheir permeability in response to mechanical stress (Morris et al. 2006; Moris andJuranka 2007; Morris and Laitko 2007). For example mechanosensitivity of NaV

channels (Moris and Juranka 2007), CaV channels (Calabrese et al. 2002), and KV

channels (Piao et al. 2006) has been convincingly shown. Definition of this termin such way allows further division of MSCs into two groups—mechanosensitivevoltage-gated channels and mechanosensitive ligand-gated channels (Kamkin andKiseleva 2008). MGCs convert the mechanical force, which is exerted on the cellmembrane, into electrical signals. Cellular signaling in response to mechanical stressstarts rapid induction of immediate-early genes, which acts as transcription factors,and triggers long-term changes in gene expression. However, the plasma membraneof the cell remains the primary target for mechanical stimulation. It responds tovariable physical stress with changes of the open probability of MGCs. MGCs can

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produce considerable currents in cells and therefore play an important role in formingtheir electric response. Both mechanosensitivity and mechanotransduction are fun-damental physiological processes which are responsible for sensing of mechanicalforces and their transformation into electrical or (and) biochemical signals.

Today many channels have been recognized as being MGCs, and include theprokaryotic MGSs of large, small, mini conductance and potassium dependent(MscL, MscS, MscM and MscK, respectively), the eukaryotic transient receptorpotential (TRP) type cation channels (TRPC6, TRPV4, TRPY1), 2P-type potassiumchannels (TREK-1, TREK-2, TRAAK) and sodium channels from DEG/MEC/ENaCfamily (ENaC, MEC4/MEC10).

The structure and function of prokaryotic MGCs MscL and MscS have providedus with much of what we know today. Thus the first part of the volume is openedwith an article devoted transmission of force from lipids. The manuscript employsa multidisciplinary approach to study of bacterial mechanosensitive ion channels(Cranfield et al. 2013). Authors stress that much of what we know about struc-ture and function of these channels derives mostly from prokaryotic sources andfrom patch clamp electrophysiology techniques and X-ray crystallography. Thenauthors describe new investigation techniques such as electron paramagnetic reso-nance (EPR) spectroscopy, förster resonance energy transfer (FRET) imaging andnuclear magnetic resonance (NMR) spectroscopy. Authors discuss those methodsalong with possible data, which can be acquired by them, for better understandingof the molecular principles underlying mechanosensory transduction in living cells.

Now it seems important to discuss a number of topics, linked to the role of K2P

channels, which determine the basal level of leak K+ ions and therefore influencesresting potential, since a number of such channels is sensitive to mechanical stress.About 10 years ago, the identification of K2P channels experimentally proved theexistence of “leak channels”, which were predicted to underlie the basal leakageof K+ by Hodgkin and Huxley in 1952. Recently a new member of this family isidentified. It consists of two 2TM/1P region-containing subunits, linked in tandem,and its functional channel is a dimer of the 4TM/2P subunits.

Several K2P channels have been recently cloned. Three of them: K2P2.1 (TREK-1),K2P10.1 (TREK-2), K2P4.1 (TRAAK) can be activated by mechanical stress. Previ-ously it has been shown in the inside–out patch configuration that positive pressure issignificantly less effective, compared with negative pressure, in opening of channels,suggesting that a specific membrane deformation (convex curving) preferentiallyopens these channels (Maingret et al. 1999; Patel et al. 1998). However it is quitelikely that this line of argument has the same limitations, which we already discussedearlier. This was shown for the K2P MGCs (Honoré et al. 2006).

At the whole-cell level, K2P2.1 and K2P4.1 are modulated by cellular volume. Forexample, hyperosmolarity closes the channels (Maingret et al. 2000a, b; Patel andHonoré 2001; Patel et al. 1998). Both the number of active channels and the sensitivityto mechanical stretch are strongly enhanced after treating the cell-attached patcheswith the cytoskeleton disrupting agents, colchicines and cytochalasin D (Maingretet al. 1999). This suggest that mechanical force might be transmitted directly to thechannel via the lipid bilayer and does not require the integrity of the cytoskeleton

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(Maingret et al. 1999; Patel et al. 1998, 2001). Both K2P2.1 and K2P4.1 are blockedby amiloride and Gd3+ (Maingret et al. 1999, 2000a, b).

In general the observation that channels, which are responsible for generation ofK+-leak current, can be activated by mechanical stress, suggests their direct contri-bution to regulation of cellular functions, one of which would be the maintenanceof the resting membrane potential. Thus the second part of the volume is openedwith an article devoted to mechanosensitive K2P channels, TREKking through theautonomic nervous system (Lamas 2013). TREK channels are leak potassium chan-nels that are extensively expressed in the central, somatic peripheral and as recentlydemonstrated in the autonomic nervous system, where they are thought to play animportant role in the modulation of neuronal excitability.

Two chapters are devoted to transient receptor potential vanilloid (TRPV1 andTRPV4) channels role in cell signaling. First of those two chapters demonstratesthat the TRPV1 channel is a polymodal receptor that has been implicated in severalphysiological and pathological processes. TRPV1 channel can be directly activatedby acidic pH, bioactive lipids, cysteine-modifying molecules, extracellular cations,voltage, elevated temperatures and several exogenous molecules such as capsaicinand toxins from animals. Its function can be modulated by the action of proteinkinases, lipids, the cytoskeleton, second messengers and many proteins involved insignaling processes (Jara-Oseguera and Rosenbaum 2013).

The second review deals with the molecular mechanism of multifunctional MGCTRPV4. TRPV4 is functionally active in many tissues, including nerve, bone, lung,kidney and blood vessels. TRPV4 is a direct MGC, and cytoskeleton proteins suchas actin, tubulin and integrin bind to the channel, helping it to respond to mechanicalstimuli (Suzuki and Mizuno 2013).

Following Fifth Chapter discusses mechanical stretch and intermediate-conductance Ca2+-activated K+ channels (Hayabuchi et al. 2013). Authors describethe role and regulation of intermediate-conductance Ca2+ -activated K+ (IKca) chan-nels in cardiovascular pathophysiologies such as hypertension and restenosis. Cellmembrane stretch activates IKca channels. The activation is associated with extra-cellular Ca2+ influx through stretch-activated nonselective cation channels, and isalso modulated by the F-actin cytoskeleton and the activation of PKC. In this reviewauthors discuss the physiological and pathophysiological role of IKca channel incells.

Chapter 6 is devoted to sensing mechanism of stretch activated ion channels (Ni-isato and Marunaka 2013) and summarizes our current knowledge of MGCs. Itdemonstrates that physical force including osmotic pressure, hydrostatic pressure,gravity, shear stress and membrane tension is a crucial signal to control cellularfunctions such as proliferation, differentiation, development and cell death. Chap-ter includes the discussion of prokaryotic MGSs—MscL and MscS, the eukaryoticTRP channels (TRPV, TRPM, TRPC, TRPP), Degenerin/epithelial Na+ channel(DEG/ENaC) superfamily—ASIC (acid-sensing ion channel), ENaC (epithelial Na+channel), MGCs in renal tubules.

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Chapter 7 is devoted to ion channels in cardiac fibroblasts.Authors separatelydiscuss MGCs and their regulation. Authors highlight that discussion of mecha-nisms of generation of mechanically induced potentials (MIPs) in cardiac fibroblastsis impossible without consideration of other membrane ion channels, which arepresent in those cells (Abramochkin et al. 2013). Cardiac fibroblasts generate delayedrectifier current (IK), transient potassium current (Ito), inward rectifier potassium cur-rent (IKir), Ca2+-activated K+ current (IK(Ca)), TTX-sensitive sodium voltage-gatedcurrent (INa.TTX), TTX-sensitive sodium voltage-gated current (INa.TTXR), volume-sensitive chloride current (ICl.vol), voltage gated proton current (IHv), non-selectivecation currents, besides mechanosensitive MG currents. Manuscript describes sin-gle mechanically gated channels (MGCs), recorded simultaneously with whole cellMG currents. All of those currents, which are mentioned above, together with MGcurrents contribute to alterations of fibroblast membrane potential (resting potentialsand MIPs).

Following Chap. 8 discusses the role of nitric oxide in the regulation of ion chan-nels in the cardiomyocytes. It describes regulation of MGCs conduction via NO.This manuscript shows that in description of the cardiac function under normal orpathological conditions separate consideration of nitric oxide effects on mechani-cally gated channels aside from consideration of its simultaneous effect on voltagegated channels of cardiac cell would be misleading (Makarenko et al. 2013). Chapterfocuses on discussion of the modulatory effect of nitric oxide on voltage gated Na+-,Ca2+-, K+-channels, which are the major contributors to generation of cardiac actionpotential and alterations of its shape under normal or pathological conditions. It alsodescribes the effect of nitric oxide on leak channels (two-pore potassium channels),some of which are known to be mechabosensitive. It is concluded with discussionof nitric oxide effects on mechanically gated ion channels and mechanically gatedcurrents.

Chapter 9 describes the role of ion channels in cellular mechanotransduction ofhydrostatic pressure. Studies reviewed herein suggest that multiple mammalian celltypes are sensitive to pure hydrostatic pressure within normal physiological ranges,and the signals may be mediated by activities of membrane-bound ion channelsand transporters (Champaigne and Nagatomi 2013). The lack of success thus farin identifying a single hydrostatic pressure-sensitive protein structure or complex,such as an ion channel, implies that the mechanosensation process of hydrostaticpressure is likely to be a multifaceted process that exploits an unconventional sensingmechanism.

Chapter 10 discusses lipid-mediated mechanisms involved in the mechanical ac-tivation of TRPC6 and TRPV4 channels in the vascular tone regulation (Inoue et al.2013). In this review, authors focus on the lipid-mediated regulation of two TRP chan-nels abundantly expressed in the cardiovascular system, i.e. TRPC6 and TRPV4, withparticular interest in the synergistic interaction between receptor-mediated and me-chanical stimulations, and discuss their complex functional antagonism in vasculartone and blood pressure regulation.

Following chapter is devoted to stretch effects on atrial conduction (Masè andRavelli 2013). In this chapter authors discuss the experimental and clinical evidence

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which supports the role of stretch-induced conduction disturbances in the creation ofan arrhythmic substrate. After an introduction concerning the methodological chal-lenges and technical advancements involved in the investigation, the effects of acutestretch on macroscopic conduction properties are described along with the potentialmicroscopic determinants of the observed changes. The mechanisms through whichstretch-induced conduction changes may contribute to the generation, maintenanceand stabilization of arrhythmic conditions are pointed out, complementing the ef-fects on conduction produced by acute stretch with the even more deleterious changesinduced by chronic dilatation.

Then the reader will find the discussion of early activation of intracellular sig-nals after myocardial stretch (Cingolani et al. 2013). Authors present the updatedexperimental evidence that led them to propose the autocrine/paracrine mechanismunderlying the Anrep effect, as well as its resemblance to signals that have been de-scribed for cardiac hypertrophy development and heart failure. Interesting novel datasupporting a crucial role for stretch-induced mineralocorticoid receptor activation,EGFR transactivation and increased mitochondrial production of reactive oxygenspecies leading to NHE-1 stimulation is thoroughly described. A clear understand-ing of the early triggering mechanisms that stretch imposes to the myocardium allowsto design novel weapons to win the battle against cardiac hypertrophy and failure, amajor disease spread worldwide.

The following chapter describes recent findings regarding effects of angiotensinII action in the heart (De Mello 2013). The influence of angiotensin II (Ang II)on cardiac structural and electrophysiological remodeling is reviewed includingthe novel concept that the renin angiotensin aldosterone and the mineralocorticoidreceptors are involved in the regulation heart cell volume. The role of Ang II AT1receptors as mechanosensors which are activated by mechanic stretch independentlyof Ang II, is discussed. The effect of Ang II and renin on cell volume and theconsequent activation of ionic channels is reviewed as well as its implications tocardiac arrhythmias (De Mello 2013).

After that the Volume includes the description of mechanosensitivity of pancre-atic β-cells, adipocytes, and skeletal muscle cells (Nakayama et al. 2013). Pancreaticβ-cells, adipocytes, and skeletal muscle cells, all of which are related to the core con-cerns in metabolic syndrome causing cardiovascular diseases, are also responsive tomechanical stimuli, such as osmotic change and stretching, and show a variety offunctions, including insulin release from β-cells, depression of adipocyte differ-entiation, and translocation of glucose transporter 4 (GLUT4) in skeletal musclecells. Furthermore, the fish-oil-derived ω-3 polyunsaturated fatty acid such as eicos-apentaenoic acid (EPA) combined with cyclic stretching significantly reduces theadipocyte differentiation. The present article provides with a unitary discussion ofthree peripheral organs from the viewpoint of mechanosensitivity, which aids in rec-ognizing the importance of biomechanical factors in physiological and pathologicalconditions, and may potentially have therapeutic consequences.

The final chapte of the Volume is devoted to the role of the primary cilium in chon-drocyte response to mechanical loading (Wann et al. 2013). Articular cartilage, likemany other living tissues, experiences a complex physiological mechanical loading

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environment which regulates cell function and tissue homeostasis through a processof mechanotransduction. This chapter explores the rapidly evolving area of primarycilia and their response to mechanical forces with a particular focus on articularcartilage for which mechanical loading is critical for homeostasis and functionality.Understanding the role of the primary cilium in mechanobiology will aid the devel-opment of novel therapeutic strategies for pathologies, such as osteoarthritis, thatinvolve disruption of primary cilia function.

Thus, the volume dwells on the major issues of mechanical stress influencing theion channels and intracellular signaling pathways. This book is a unique collection ofreviews outlining current knowledge and future developments in this rapidly growingfield. In our opinion the book presents not only the latest achievements in the fieldbut also brings the problem closer to the experts in related medical and biologicalsciences as well as practicing doctors. Knowledge of the mechanisms which underliethese processes is necessary for understanding of the normal functioning of differentliving organs and tissues and allows to predict changes, which arise due to alterationsof their environment, and possibly will allow to develop new methods of artificialintervention. We also hope that presenting the problem will attract more attention toit both from researchers and practitioners and will assist to efficiently introduce itinto the practical medicine.

References

Abramochkin DV, Lozinsky I, KamkinA (2013) Ion channels in cardiac fibroblasts: Link to mechan-ically gated channels and their regulation. In: Kamkin A, Lozinsky I (eds) Mechanosensitivityin cells and tissues 6. Mechanically gated channels and their regulation. Springer, Berlin

Calabrese B, Tabarean IV, Juranka P, Morris CE (2002) Mechanosensitivity of N-type calciumchannel currents. Biophys J 83(5):2560–2574

Champaigne KD, Nagatomi J (2013) The role of ion channels in cellular mechanotransduction ofhydrostatic pressure. In: Kamkin A, Lozinsky I (eds) Mechanosensitivity in cells and tissues 6.Mechanically gated channels and their regulation. Springer, Berlin

Cingolani HE, Villa-Abrille MC, Caldiz CI, Ennis IL, Cingolani OH, Morgan PE, Aiello EA,Pérez NG (2013) Early activation of intracellular signals after myocardial stretch: Anrep effect,myocardial hypertrophy and heart failure. In: Kamkin A, Lozinsky I (eds) Mechanosensitivityin cells and tissues 6. Mechanically gated channels and their regulation. Springer, Berlin

Cranfield CG, Kloda A, Nomura T, Petrov E, Battle A, Constantine M, Martinac B (2013) Forcefrom lipids: a multidisciplinary approach to study bacterial mechanosensitive ion channels.In: Kamkin A, Lozinsky I (eds) Mechanosensitivity in cells and tissues 6. Mechanically gatedchannels and their regulation. Springer, Berlin, pp 1–33

De MelloWC (2013) Recent aspects of angiotensin II action in the heart. Implications for myocardialischemia and heart failure. In: KamkinA, Lozinsky I (eds) Mechanosensitivity in cells and tissues6. Mechanically gated channels and their regulation. Springer, Berlin, pp 367–378

Guharay F, Sachs F (1984) Stretch-activated single ion channel currents in tissue cultured embryonicchick skeletal muscle. J Physiol (Lond) 352:685–701

Hayabuchi Y, Sakata M, Ohnishi T, Kagami S (2013) Mechanical stretch and intermediate-conductance Ca2+-activated K+ channels in arterial smooth muscle cells. In: Kamkin A,Lozinsky I (eds) Mechanosensitivity in cells and tissues 6. Mechanically gated channels andtheir regulation. Springer, Berlin, pp 159–187

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Honoré E, Patel AJ, Chemin J, Suchyna T, Sachs F (2006) Desensitization of mechano-gated K2Pchannels. Proc Natl Acad Sci USA 103(18):6859–6864

Inoue R, Hu Y, Duan Y, Itsuki K (2013) Lipid-mediated mechanisms involved in the mechanicalactivation of TRPC6 and TRPV4 channels in the vascular tone regulation. In: Kamkin A, Lozin-sky I (eds) Mechanosensitivity in cells and tissues 6. Mechanically gated channels and theirregulation. Springer, Berlin, pp 281–301

Jara-Oseguera A, Rosenbaum T (2013) TRPV1 in cell signaling: molecular mechanisms of functionand modulation. In: Kamkin A, Lozinsky I (eds) Mechanosensitivity in cells and tissues 6.Mechanically gated channels and their regulation. Springer, Berlin, pp 69–102

Kamkin A, Kircheis R, Kiseleva I (1986) New type of cell in the frog atria? In: Challenges inprevention, diagnostics and treatment of cardio-vascular diseases. Springer, Moscow. p. 11

Kamkin A, Kiseleva I (2008) Mechanically gated channels and mechanosensitive channels. In:Kamkin A, Kiseleva I (eds) Mechanosensitivity in cells and tissues. mechanosensitive ionchannels. Springer, Berlin, pp xiii–xviii

Kamkin A, Kiseleva I, Kircheis R, Kositzky G (1988) Bioelectric activity of frog atrium cellswith non-typical impulse acvity. Abhandlungen der Akademie der Wissenschaften der DDR(Abteilung Mathematik – Naturwissenschaft – Technik) 1:103–106

Kaufmann R, Theophile U (1967) Autonomously promoted extension effect in Purkinje fibers,papillary muscles and trabeculae carneae of rhesus monkeys. Pflugers Arch Gesamte PhysiolMenschen Tiere 297(3):174–189

Kirber MT, Ordway RW, Clapp LH, Sims SM, Walsh JV Jr, Singer JJ (1990) Voltage, ligand, andmechanically gated channels in freshly dissociated single smooth muscle cells. Prog Clin BiolRes 334:123–143

Kiseleva IS, Kamkin AG, Kircheis R, Kositski GI (1987) Intercellular electrotonical interaction inthe cardiac sinus node in the frog. Reports of Academy of Science of USSR 292(6):1502–1505

Lab MJ (1968) Is there mechano-electric transduction in cardiac muscle? The monophasic actionpotential of the frog ventricle during isometric and isotonic contraction with calcium deficientperfusions. S Afr J Med Sci 33:60

Lamas JA (2013) Mechanosensitive K2P channels, TREKking through the autonomic nervoussystem. In: KamkinA, Lozinsky I (eds) Mechanosensitivity in Cells and Tissues 6. Mechanicallygated channels and their regulation. Springer, Berlin, pp 35–68

Maingret F, Fosset M, Lesage F, Lazdunski M, Honore E (1999) TRAAK is a mammalian neuronalmechano-gated K+ channel. J Biol Chem 274:1381–1387

Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honore E (2000a)TREK-1–1 is a heat-activated background K+ channel. EMBO J 19:2483–2491

Maingret F, Patel AJ, Lesage F, Lazdunski M, Honoré E (2000b) Lysophospholipids open the twoP domain mechano-gated K+ channels TREK-1 and TRAAK. J Biol Chem 275:10128–10133

Makarenko EYu, Lozinsky I, Kamkin A (2013) The role of nitric oxide in the regulation of ionchannels in the cardiomyocytes: Link to mechanically gated channels. In: Kamkin A, Lozinsky I(eds) Mechanosensitivity in cells and tissues 6. Mechanically gated channels and their regulation.Springer, pp 245–262

Masè M, Ravelli F (2013) Stretch effects on atrial conduction: a potential contributor to arrhythmo-genesis. In: Kamkin A, Lozinsky I (eds) Mechanosensitivity in cells and tissues 6. Mechanicallygated channels and their regulation. Springer, Berlin, pp 303–325

Moris CE, Juranka PF (2007) NaV channel mechanosensitivity: activation and inactivationaccelerate reversibly with stretch. Biophys J 93(3):822–833

Morris CE, Laitko U (2007) The mechanosensitivity of voltage-gated channels may contribute tocardiac mechano-electric feedback. In: Kohl P, Franz MR, Sachs F (eds) Cardiac mechano-electrical feedback and arrhythmias: from pipette to patient. Saunders, Philadelphia, pp 33–41

Morris CE, Juranka PF, Lin W, Morris TJ, Laitko U (2006) Studying the mechanosensitivity ofvoltage-gated channels using oocyte patches. Methods Mol Biol 322:315–329

Nakayama K, Tanabe Y, Obara K, Ishikawa T (2013) Mechanosensitivity of pancreatic β-cells,adipocytes, and skeletal muscle cells: the therapeutic targets of metabolic syndrome. In: KamkinA, Lozinsky I (eds) Mechanosensitivity in cells and tissues 6. Mechanically gated channels andtheir regulation. Springer, Berlin, pp 379–403

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Niisato N, Marunaka Y (2013) Sensing mechanism of stretch activated ion channels. In: KamkinA,Lozinsky I (eds) Mechanosensitivity in cells and tissues 6. Mechanically gated channels andtheir regulation. Springer, Berlin, pp 189–213

Patel AJ, Honoré E (2001) Properties and modulation of mammalian 2P domain K+ channels.TRENDS Neurosci 24(6):339–345

Patel AJ, Honoré E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M (1998) A mammaliantwo pore domain mechano-gated s-like K+ channel. EMBO J 17:4283–4290

Piao L, Li HY, Park CK, Cho IH, Piao ZG, Jung SJ, Choi SY, Lee SJ, Park K, Kim JS, Oh SB(2006) Mechanosensitivity of voltage-gated K+ currents in rat trigeminal ganglion neurons. JNeurosci Res 83(7):1373–1380

Sachs F, Morris CE (1998) Mechanosensitive ion channels in nonspecialized cells. Rev PhysiolBiochem Pharmacol 132:1–77

Suzuki M, MizunoA (2013) The Molecular Mechanism of Multifunctional Mechano-Gated ChannelTRPV4. In: Kamkin A, Lozinsky I (eds) Mechanosensitivity in cells and tissues 6. Mechanicallygated channels and their regulation. Springer, Berlin, pp 103–157

Wann AKT, Thompson CL, Knight MM (2013) The role of the primary cilium in chondrocyteresponse to mechanical loading. In: Kamkin A, Lozinsky I (eds) Mechanosensitivity in cellsand tissues 6. Mechanically gated channels and their regulation. Springer, Berlin, pp 405–426

Contents

1 Force from Lipids: A Multidisciplinary Approach to Study BacterialMechanosensitive Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Charles G. Cranfield, Anna Kloda, Takeshi Nomura, Evgeny Petrov,Andrew Battle, Maryrose Constantine and Boris Martinac

2 Mechanosensitive K2P channels, TREKking through the autonomicnervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35J. Antonio Lamas

3 TRPV1 in Cell Signaling: Molecular Mechanisms of Functionand Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Andrés Jara-Oseguera and Tamara Rosenbaum

4 The Molecular Mechanism of Multifunctional Mechano-GatedChannel TRPV4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103Makoto Suzuki and Astuko Mizuno

5 Mechanical Stretch and Intermediate-Conductance Ca2+-ActivatedK+ Channels in Arterial Smooth Muscle Cells . . . . . . . . . . . . . . . . . . . . . 159Yasunobu Hayabuchi, Miho Sakata, Tatsuya Ohnishi and Shoji Kagami

6 Sensing Mechanism of Stretch Activated Ion Channels . . . . . . . . . . . . . 189Naomi Niisato and Yoshinori Marunaka

7 Ion Channels in Cardiac Fibroblasts: Link to Mechanically GatedChannels and their Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Denis V. Abramochkin, Ilya Lozinsky and Andre Kamkin

8 The Role of Nitric Oxide in the Regulation of Ion Channels in theCardiomyocytes: Link to Mechanically Gated Channels . . . . . . . . . . . . 245Ekaterina Yu. Makarenko, Ilya Lozinsky and Andre Kamkin

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9 The Role of Ion Channels in Cellular Mechanotransductionof Hydrostatic Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263Kevin D. Champaigne and Jiro Nagatomi

10 Lipid-Mediated Mechanisms Involved in the Mechanical Activationof TRPC6 and TRPV4 Channels in the Vascular Tone Regulation . . . . 281Ryuji Inoue, Yaopeng Hu, Yubin Duan and Kyohei Itsuki

11 Stretch Effects on Atrial Conduction: A Potential Contributorto Arrhythmogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303Michela Masè and Flavia Ravelli

12 Early Activation of Intracellular Signals after Myocardial Stretch:Anrep Effect, Myocardial Hypertrophy and Heart Failure . . . . . . . . . . 327Horacio E. Cingolani, María C. Villa-Abrille, Claudia I. Caldiz,Irene L. Ennis, Oscar H. Cingolani, Patricio E. Morgan,Ernesto A. Aiello and Néstor Gustavo Pérez

13 Recent Aspects of Angiotensin II Action in the Heart. Implicationsfor Myocardial Ischemia and Heart Failure . . . . . . . . . . . . . . . . . . . . . . . 367Walmor C. De Mello

14 Mechanosensitivity of Pancreatic β-cells, Adipocytes, and SkeletalMuscle Cells: The Therapeutic Targets of Metabolic Syndrome . . . . . . 379Koichi Nakayama, Yoshiyuki Tanabe, Kazuo Obaraand Tomohisa Ishikawa

15 The Role of the Primary Cilium in Chondrocyte Responseto Mechanical Loading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405Angus K. T. Wann, Clare Thompson and Martin M. Knight

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

Contributors

Denis V. Abramochkin Department of Fundamental andApplied Physiology, Lab-oratory of Electrophysiology, Russian State Medical University, Ostrovitjanova 1,Moscow 117997, Russia

Ernesto A. Aiello Centro de Investigaciones Cardiovasculares, Facultad de Cien-cias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata,Argentina

Andrew Battle School of Pharmacy, Griffith University, Gold Coast Campus, QLD4022, Australia

Claudia I. Caldiz Centro de Investigaciones Cardiovasculares, Facultad de Cien-cias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata,Argentina

Kevin D. Champaigne Department of Bioengineering, Clemson University, 315Rhodes Hall, Clemson, SC 29634-0905, USA

Horacio E. Cingolani Centro de Investigaciones Cardiovasculares, Facultad deCiencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata,Argentinae-mail: cicmes@infovia.com.ar

Oscar H. Cingolani Division of Cardiology, Johns Hopkins University Hospital,720 Rutland Avenue, Ross 835, Baltimore, MD 21205, USA

Maryrose Constantine Mechanosensory Biophysics Laboratory, Molecular Car-diology and Biophysics Division, Victor Chang Cardiac Research Institute, 405Liverpool St, Darlinghurst, NSW 2010, Australia

Charles G. Cranfield Mechanosensory Biophysics Laboratory, Molecular Car-diology and Biophysics Division, Victor Chang Cardiac Research Institute,405 Liverpool St, Darlinghurst, NSW 2010, Australiae-mail: c.cranfield@victorchang.edu.au

xvii

xviii Contributors

Walmor C. De Mello Department of Pharmacology, School of Medicine, MedicalSciences Campus, UPR, San Juan, PR 00936-5067, USAe-mail: walmor.de-mello@upr.edu

Yubin Duan Department of Physiology, Graduate School of Medical Sciences,Fukuoka University, Fukuoka 814-0180, Japan

Irene L. Ennis Centro de Investigaciones Cardiovasculares, Facultad de CienciasMédicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata, Argentina

Yasunobu Hayabuchi Department of Pediatrics, University of Tokushima,Kuramoto-cho-3-18-15, Tokushima 770-8503, Japane-mail: hayabuchi@clin.med.tokushima-u.ac.jp

Yaopeng Hu Department of Physiology, Graduate School of Medical Sciences,Fukuoka University, Fukuoka 814-0180, Japan

Ryuji Inoue Department of Physiology, Graduate School of Medical Sciences,Fukuoka University, Fukuoka 814-0180, Japane-mail: inouery@fukuoka-u.ac.jp

Tomohisa Ishikawa Department of Pharmacology, School of Pharmaceutical Sci-ences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka422-8526, Japan

Kyohei Itsuki Department of Physiology, Graduate School of Medical Sciences,Fukuoka University, Fukuoka 814-0180, Japan

Andrés Jara-Oseguera Departamento de Fisiología, Facultad de Medicina, Uni-versidad Nacional Autónoma de México, D.F., México

Shoji Kagami Department of Pediatrics, University of Tokushima, Kuramoto-cho-3-18-15, Tokushima 770-8503, Japan

Andre Kamkin Department of Fundamental and Applied Physiology, Laboratoryof Electrophysiology, Russian State Medical University, Ostrovitjanova 1, Moscow117997, Russiae-mail: Kamkin.A@g23.relcom.ru

Anna Kloda School of Biomedical Sciences, The University of Queensland, StLucia, QLD 4072, Australia

Martin M. Knight Institute of Bioengineering, School of Engineering and Mate-rials Science, Queen Mary University of London, Mile End Rd, E1 4NS, London,UK

J. Antonio Lamas Laboratory of Neuroscience, CINBIO, Department of Func-tional Biology, University of Vigo, 36310 Vigo, Spaine-mail: antoniolamas@uvigo.es

Contributors xix

Ilya Lozinsky Department of Fundamental and Applied Physiology, Laboratoryof Electrophysiology, Russian State Medical University, Ostrovitjanova 1, Moscow117997, Russia

Ekaterina Yu. Makarenko Department of Fundamental and Applied Physiology,Laboratory of Electrophysiology, Russian State Medical University, Ostrovitjanova1, Moscow 117997, Russia

Boris Martinac Mechanosensory Biophysics Laboratory, Molecular Cardiologyand Biophysics Division, Victor Chang Cardiac Research Institute, 405 LiverpoolSt, Darlinghurst, NSW 2010, Australia

Yoshinori Marunaka Department of Molecular Cell Physiology, Graduate Schoolof Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566,Japan

Michela Masè Laboratory of Biophysics and Biosignals and BIOTech, Departmentof Physics, Faculty of Science, University of Trento, Via Sommarive 14, 38123,Povo-Trento, Italye-mail: mase@science.unitn.it

Astuko Mizuno Department of Molecular Pharmacology, Jichi Medical university,Yakushiji 3311-1, Tochigi, Japan

Patricio E. Morgan Centro de Investigaciones Cardiovasculares, Facultad de Cien-cias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata,Argentina

Jiro Nagatomi Department of Bioengineering, Clemson University, 315 RhodesHall, Clemson, SC 29634-0905, USAe-mail: jnagato@clemson.edu

Koichi Nakayama Department of Molecular and Cellular Pharmacology, Facultyof Pharmaceutical Sciences, Iwate Medical University, Yahaba, Iwate 028-3694,Japane-mail: nakyamk@iwate-med.ac.jp

Naomi Niisato Department of Molecular Cell Physiology, Graduate School ofMedical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japane-mail: naomi@koto.kpu-m.ac.jp

Takeshi Nomura Mechanosensory Biophysics Laboratory, Molecular Cardiologyand Biophysics Division, Victor Chang Cardiac Research Institute, 405 LiverpoolSt, Darlinghurst, NSW 2010, Australia

Kazuo Obara Department of Pharmacology, School of Pharmaceutical Sciences,University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526,Japan

Tatsuya Ohnishi Department of Pediatrics, University of Tokushima, Kuramoto-cho-3-18-15, Tokushima 770-8503, Japan

xx Contributors

Néstor Gustavo Pérez Centro de Investigaciones Cardiovasculares, Facultad deCiencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata,Argentina

Evgeny Petrov Mechanosensory Biophysics Laboratory, Molecular Cardiologyand Biophysics Division, Victor Chang Cardiac Research Institute, 405 LiverpoolSt, Darlinghurst, NSW 2010, Australia

Flavia Ravelli Laboratory of Biophysics and Biosignals and BIOTech, Departmentof Physics, Faculty of Science, University of Trento, Via Sommarive 14, 38123,Povo-Trento, Italye-mail: ravelli@science.unitn.it

Tamara Rosenbaum Departamento de Neurodesarrollo y Fisiología, División Neu-rociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma deMéxico, México, D. F., Méxicoe-mail: trosenba@ifc.unam.mx

Miho Sakata Department of Pediatrics, University of Tokushima, Kuramoto-cho-3-18-15, Tokushima 770-8503, Japan

Makoto Suzuki Edogawabashi clinic, 348 Yamabuki, Shinjyuku, Tokyo, Japane-mail: msuzuki@edogawabashi-clinic.com

Yoshiyuki Tanabe Department of Molecular and Cellular Pharmacology, Facultyof Pharmaceutical Sciences, Iwate Medical University, Yahaba, Iwate 028-3694,Japan

Clare Thompson Institute of Bioengineering, School of Engineering and MaterialsScience, Queen Mary University of London, Mile End Rd, E1 4NS, London, UK

María C. Villa-Abrille Centro de Investigaciones Cardiovasculares, Facultad deCiencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata,Argentina

Angus K. T. Wann Institute of Bioengineering, School of Engineering and Materi-als Science, Queen Mary University of London, Mile End Rd, E1 4NS, London, UKe-mail: m.m.knight@qmul.ac.uk