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  • Print publication year: 2009
  • Online publication date: July 2014

4 - Mechanotransduction by Membrane-Mediated Activation of G-Protein Coupled Receptors and G-Proteins



Atherosclerosis, the leading cause of death in the Western world and nearly the leading cause in other developing countries, is associated with systemic risk factors such as hypertension, smoking, diabetes mellitus, and hyperlipidemia (Malek et al., 1999a). Nonetheless, it is clearly a focal disease with atherosclerotic lesions forming in the coronary arteries, major branches of the aortic arch, and the abdominal aorta. Plaque formation preferentially involves the outer walls of vessel bifurcations and points of blood flow recirculation, where hemodynamic shear stress is weaker than in unaffected areas. Detailed analysis of fluid mechanics in these areas revealed a strong spatial correlation between endothelial dysfunction/plaque formation and low mean shear stress and oscillatory flow with recirculation (Nerem, 1992; Malek et al., 1999a). It has been suggested that low mean shear stress and nonlaminar flow stimulate the formation of an atherogenic phenotype (Gibson et al., 1993; Ku et al., 1985) while arterial level shear stress (≥15 dynes/cm2) stimulates atheroprotective gene expression profile and cellular responses that are essential for normal endothelial function (Harrison, 2005; Cunningham and Gotlieb, 2005), implying that the maintenance of physiological, laminar shear stress on endothelial cells is crucial for normal vascular function (Traub and Berk, 1998). The development of atherogenesis can be studied at various levels; however, the origins of the disease have been linked to mechanosensing by a number of studies (Ku et al., 1985; Glagov et al., 1988; Svindland, 1983; Debakey et al., 1985; White et al., 2003), suggesting that investigations at the molecular level are required for further understanding of the atherogenesis.

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Abdul-Rahim, H and Bouchy, M (1998) Analysis of the Fluorescence Anisotropy of Labelled Membranes Submitted to a Shear Stress. J Photochem Photobiol B 47: 95–108.
Arnold, K, Zschoernig, O, Barthel, D and Herold, W (1990) Exclusion of Poly (Ethylene Glycol) From Liposome Surfaces. Biochimica et Biophysica Acta 1022: 303–310.
Azpiazu, I and Gautam, N (2004) A Fluorescence Resonance Energy Transfer-Based Sensor Indicates That Receptor Access to a G-protein Is Unrestricted in a Living Mammalian Cell. J Biol Chem 279: 27709–27718.
Bagatolli, L A and Gratton, E (2000) Two Photon Fluorescence Microscopy of Coexisting Lipid Domains in Giant Unilamellar Vesicles of Binary Phospholipid Mixtures. Biophys J 78: 290–305.
Bagatolli, L A, Gratton, E and Fidelio, G D (1998) Water Dynamics in Glycosphingolipid Aggregates Studied by LAURDAN Fluorescence. Biophys J 75: 331–341.
Bao, X, Clark, C B and Frangos, J A (2000) Temporal Gradient in Shear-Induced Signaling Pathway: Involvement of MAP Kinase, C-Fos, and Connexin4319. Am J Physiol Heart Circ Physiol 278: H1598–H1605.
Baskin, J S, Chachisvilis, M, Gupta, M and Zewail, A H (1998) Femtosecond Dynamics of Solvation: Microscopic Friction and Coherent Motion in Dense Fluids. J Phys Chem A 102: 4158–4171.
Ben-Shaul, A (1995) in Structure and Dynamics of Membranes (Lipowsky, R and Sackman, E, eds.), pp. 359–401, Elsevier, Amsterdam.
Bergaya, S, Meneton, P, Bloch-Faure, M, Mathieu, E, Alhenc-Gelas, F, Levy, B I and Boulanger, C M (2001) Decreased Flow-Dependent Dilation in Carotid Arteries of Tissue Kallikrein-Knockout Mice. Circ Res 88: 593–599.
Berk, B C, Abe, J I, Min, W, Surapisitchat, J and Yan, C (2001) Endothelial Atheroprotective and Anti-Inflammatory Mechanisms. Ann NY Acad Sci 947: 93–109.
Bevan, J A, Kaley, G and Rubanyi, G M (1995) Flow-Dependent Regulation of Vascular Function. Oxford University Press, New York.
Blood, P D, Ayton, G S and Voth, G A (2005) Probing the Molecular-Scale Lipid Bilayer Response to Shear Flow Using Nonequilibrium Molecular Dynamics. J Phys Chem B 109: 18673–18679.
Boo, Y C and Jo, H (2003) Flow-Dependent Regulation of Endothelial Nitric Oxide Synthase: Role of Protein Kinases. Am J Physiol Cell Physiol 285: C499–C508.
Boo, Y C, Hwang, J, Sykes, M, Michell, B J, Kemp, B E, Lum, H and Jo, H (2002a) Shear Stress Stimulates Phosphorylation of ENOS at Ser (635) by a Protein Kinase A-Dependent Mechanism. Am J Physiol Heart Circ Physiol 283: H1819–H1828.
Boo, Y C, Sorescu, G, Boyd, N, Shiojima, I, Walsh, K, Du, J and Jo, H (2002b) Shear Stress Stimulates Phosphorylation of Endothelial Nitric-Oxide Synthase at Ser1179 by Akt-Independent Mechanisms: Role of Protein Kinase A. J Biol Chem 277: 3388–3396.
Borochov, A and Borochov, H (1979) Increase in Membrane Fluidity in Liposomes and Plant Protoplasts Upon Osmotic Swelling. Biochimica et Biophysica Acta 550: 546–549.
Botelho, A V, Gibson, N J, Thurmond, R L, Wang, Y and Brown, M F (2002) Conformational Energetics of Rhodopsin Modulated by Nonlamellar-Forming Lipids. Biochemistry 41: 6354–6368.
Bourne, H R (1997) How Receptors Talk to Trimeric G-proteins. Curr Opin Cell Biol 9: 134–142.
Bowie, J U (2005) Solving the Membrane Protein Folding Problem. Nature 438: 581–589.
Brochard, F and Lennon, J F (1975) Frequency Spectrum of Flicker Phenomenon in Erythrocytes. J Physique 36: 1035–1047.
Brown, D A and London, E (1998) Functions of Lipid Rafts in Biological Membranes. Ann Rev Cell and Developmental Bio 14: 111–136.
Bunemann, M, Frank, M and Lohse, M J (2003) Gi Protein Activation in Intact Cells Involves Subunit Rearrangement Rather Than Dissociation. Proceedings of the National Academy of Sciences of the United States of America 100: 16077–16082.
Butler, P J, Norwich, G, Weinbaum, S and Chien, S (2001) Shear Stress Induces a Time- and Position-Dependent Increase in Endothelial Cell Membrane Fluidity. Amer J Physiol – Cell Physiol 280: C962–C969.
Butler, P J, Tsou, T C, Li, J Y, Usami, S and Chien, S (2002) Rate Sensitivity of Shear-Induced Changes in the Lateral Diffusion of Endothelial Cell Membrane Lipids: A Role for Membrane Perturbation in Shear-Induced MAPK Activation. FASEB J 16: 216–218.
Cantor, R S (1997) Lateral Pressures in Cell Membranes: A Mechanism for Modulation of Protein Function. J Phys Chem B 101: 1723–1725.
Chachisvilis, M, Chirvony, V S, Shulga, A M, Kallebring, B, Larsson, S and Sundstrom, V (1996) Spectral and Photophysical Properties of Ethylene-Bridged Side-to-Side Porphyrin Dimers. 2. Femtosecond Transient Absorption and Picosecond Fluorescence Study of Trans-1,2-Bis (Meso-Octaethylporphyrinyl)Ethene. J Phys Chem 100: 13867–13873.
Chachisvilis, M, Zhang, Y L and Frangos, J A (2006) G-protein-Coupled Receptors Sense Fluid Shear Stress in Endothelial Cells. Proceedings of the National Academy of Sciences of the United States of America 103: 15463–15468.
Chen, A K, Latz, M I and Frangos, J A (2003) The Use of Dinoflagellate Bioluminescence to Characterize Cell Stimulation in Bioreactors. Biotechnol Bioeng 83: 93–103.
Chen, A K, Latz, M I, Sobolewski, P and Frangos, J A (2007) Evidence for the Role of G-Proteins in Flow Stimulation of Dinoflagellate Bioluminescence. Am J Physiol Regul Integr Comp Physiol.
Chen, B M and Grinnell, A D (1997) Kinetics, Ca2+ Dependence, and Biophysical Properties of Integrin-Mediated Mechanical Modulation of Transmitter Release From Frog Motor Nerve Terminals. J Neurosci 17: 904–916.
Cirino, G, Fiorucci, S and Sessa, W C (2003) Endothelial Nitric Oxide Synthase: the Cinderella of Inflammation?Trends Pharmaco Sci 24: 91–95.
Cohen, M H and Turnbull, D (1959) Molecular Transport in Liquids and Glasses. J Chem Phys 31: 1164–1169.
Criado, M, Eibl, H and Barrantes, F J (1984) Functional Properties of the Acetylcholine Receptor Incorporated in Model Lipid-Membranes – Differential Effects of Chain-Length and Head Group of Phospholipids on Receptor Affinity States and Receptor-Mediated Ion Translocation. J Bio Chem 259: 9188–9198.
Cunningham, K S and Gotlieb, A I (2005) The Role of Shear Stress in the Pathogenesis of Atherosclerosis. Lab Invest 85: 9–23.
Das, P, Schurman, D J and Smith, R L (1997) Nitric Oxide and G-proteins Mediate the Response of Bovine Articular Chondrocytes to Fluid-Induced Shear. J Orthop Res 15: 87–93.
Davies, P F (1995) Flow-Mediated Endothelial Mechanotransduction. Physiol Rev 75: 519–560.
Debakey, M E, Lawrie, G M and Glaeser, D H (1985) Patterns of Atherosclerosis and Their Surgical Significance. Annals Surgery 201: 115–131.
Detwiler, P B, Ramanathan, S, Sengupta, A and Shraiman, B I (2000) Engineering Aspects of Enzymatic Signal Transduction: Photoreceptors in the Retina. Biophys J 79: 2801–2817.
Dimmeler, S, Fleming, I, Fisslthaler, B, Hermann, C, Busse, R and Zeiher, A M (1999) Activation of Nitric Oxide Synthase in Endothelial Cells by Akt-Dependent Phosphorylation. Nature 399: 601–605.
Dixit, M, Loot, A E, Mohamed, A, Fisslthaler, B, Boulanger, C M, Ceacareanu, B, Hassid, A, Busse, R and Fleming, I (2005) Gab1, SHP2, and Protein Kinase A Are Crucial for the Activation of the Endothelial NO Synthase by Fluid Shear Stress. Circ Res 97: 1236–1244.
Doolittle, A K (1951) Studies in Newtonian Flow. II. The Dependence of the Viscosity of Liquids on Free-Space. J Appl Phys1471–1475.
Engelman, D M (2005) Membranes Are More Mosaic Than Fluid. Nature 438: 578–580.
Epand, R M (1998) Lipid Polymorphism and Protein-Lipid Interactions. Biochim Biophysi Acta – Revi Biomembranes 1376: 353–368.
Evans, E and Needham, D (1987) Physical Properties of Surfactant Bilayer Membranes – Thermal Transitions, Elasticity, Rigidity, Cohesion, and Colloidal Interactions. J Phys Chem 91: 4219–4228.
Evans, E and Rawicz, W (1990) Entropy-Driven Tension and Bending Elasticity in Condensed-Fluid Membranes. Physical Review Letters 64: 2094–2097.
Farrens, D L, Altenbach, C, Yang, K, Hubbell, W L and Khorana, H G (1996) Requirement of Rigid-Body Motion of Transmembrane Helices for Light Activation of Rhodopsin. Science 274: 768–770.
Feller, S E and Gawrisch, K (2005) Properties of Docosahexaenoic-Acid-Containing Lipids and Their Influence on the Function of Rhodopsin. Current Opinion Struct Biol 15: 416–422.
Fisslthaler, B, Dimmeler, S, Hermann, C, Busse, R and Fleming, I (2000) Phosphorylation and Activation of the Endothelial Nitric Oxide Synthase by Fluid Shear Stress. Acta Physiol Scand 168: 81–88.
Fleming, I, Fisslthaler, B, Dixit, M and Busse, R (2005) Role of PECAM-1 in the Shear-Stress-Induced Activation of Akt and the Endothelial Nitric Oxide Synthase (ENOS) in Endothelial Cells. J Cell Sci 118: 4103–4111.
Frangos, S G, Gahtan, V and Sumpio, B (1999) Localization of Atherosclerosis: Role of Hemodynamics. Arch Surg 134: 1142–1149.
Gether, U (2000) Uncovering Molecular Mechanisms Involved in Activation of G-protein-Coupled Receptors. Endocrine Reviews 21: 90–113.
Ghanouni, P, Gryczynski, Z, Steenhuis, J J, Lee, T W, Farrens, D L, Lakowicz, J R and Kobilka, B K (2001a) Functionally Different Agonists Induce Distinct Conformations in the G-protein Coupling Domain of the Beta (2) Adrenergic Receptor. J Biol Chem 276: 24433–24436.
Ghanouni, P, Steenhuis, J J, Farrens, D L and Kobilka, B K (2001b) Agonist-Induced Conformational Changes in the G-Protein-Coupling Domain of the Beta (2) Adrenergic Receptor. Proceedings of the National Academy of Sciences of the United States of America 98: 5997–6002.
Gibson, C M, Diaz, L, Kandarpa, K, Sacks, F M, Pasternak, R C, Sandor, T, Feldman, C and Stone, P H (1993) Relation of Vessel Wall Shear Stress to Atherosclerosis Progression in Human Coronary Arteries. Arterioscler Thromb 13: 310–315.
Gierschik, P, Moghtader, R, Straub, C, Dieterich, K and Jakobs, K H (1991) Signal Amplification in HL-60 Granulocytes. Evidence That the Chemotactic Peptide Receptor Catalytically Activates Guanine-Nucleotide-Binding Regulatory Proteins in Native Plasma Membranes. Eur J Biochem 197: 725–732.
Glagov, S, Zarins, C, Giddens, D P and Ku, D N (1988) Hemodynamics and Atherosclerosis – Insights and Perspectives Gained from Studies of Human Arteries. Archives of Pathology & Laboratory Medicine 112: 1018–1031.
Golser, R, Gorren, A C F, Leber, A, Andrew, P, Habisch, H J, Werner, E R, Schmidt, K, Venema, R C and Mayer, B (2000) Interaction of Endothelial and Neuronal Nitric-Oxide Syntheses With the Bradykinin B2 Receptor – Binding of an Inhibitory Peptide to the Oxygenase Domain Blocks Uncoupled NADPH Oxidation. J Bio Chem 275: 5291–5296.
Goodwin, J S, Drake, K R, Remmert, C L and Kenworthy, A K (2005) Ras Diffusion Is Sensitive to Plasma Membrane Viscosity. Biophys J 89: 1398–1410.
Gov, N S (2006) Diffusion in Curved Fluid Membranes. Physical Review 73.
Grote, R F and Hynes, J T (1980) The Stable States Picture of Chemical Reactions. 2. Rate Constants for Condensed and Gas-Phase Reaction Models. J Chem Phys 73: 2715–2732.
Grote, R F and Hynes, J T (1981) Saddle-Point Model for Atom Transfer-Reactions in Solution. J Chem Phys 75: 2191–2198.
Groves, P, Kurz, S, Just, H and Drexler, H (1995) Role of Endogenous Bradykinin in Human Coronary Vasomotor Control. Circulation 92: 3424–3430.
Gudi, S, Huvar, I, White, C R, McKnight, N L, Dusserre, N, Boss, G R and Frangos, J A (2003) Rapid Activation of Ras by Fluid Flow Is Mediated by Galpha (q) and Gbetagamma Subunits of Heterotrimeric G-proteins in Human Endothelial Cells. Arterioscler Thromb Vasc Biol 23: 994–1000.
Gudi, S, Nolan, J P and Frangos, J A (1998) Modulation of GTPase Activity of G-proteins by Fluid Shear Stress and Phospholipid Composition. Proceedings of the National Academy of Sciences of the United States of America 95: 2515–2519.
Gudi, S R P, Clark, C B and Frangos, J A (1996) Fluid Flow Rapidly Activates G-proteins in Human Endothelial Cells – Involvement of G-proteins in Mechanochemical Signal Transduction. Circ Res 79: 834–839.
Gullingsrud, J and Schulten, K (2004) Lipid Bilayer Pressure Profiles and Mechanosensitive Channel Gating. Biophys J 86: 3496–3509.
Haidekker, M A, Brady, T, Wen, K, Okada, C, Stevens, H Y, Snell, J M, Frangos, J A and Theodorakis, E A (2002) Phospholipid-Bound Molecular Rotors: Synthesis and Characterization. Bioorganic & Medicinal Chemistry 10: 3627–3636.
Haidekker, M A, L’Heureux, N and Frangos, J A (2000) Fluid Shear Stress Increases Membrane Fluidity in Endothelial Cells: A Study with DCVJ Fluorescence. Amer J Physiol – Heart and Circulatory Physiol 278: H1401–H1406.
Haidekker, M A, Ling, T T, Anglo, M, Stevens, H Y, Frangos, J A and Theodorakis, E A (2001) New Fluorescent Probes for the Measurement of Cell Membrane Viscosity. Chemistry & Biology 8: 123–131.
Haines, T H (1982) A Model for Transition-State Dynamics in Bilayers – Implications for the Role of Lipids in Biomembrane Transport. Biophys J 37: 147–148.
Hamm, H E, Deretic, D, Arendt, A, Hargrave, P A, Koenig, B and Hofmann, K P (1988) Site of G-protein Binding to Rhodopsin Mapped with Synthetic Peptides from the Alpha Subunit. Science 241: 832–835.
Hanggi, P, Talkner, P and Borkovec, M (1990) Reaction-Rate Theory – 50 Years After Kramers. Rev Modern Phys 62: 251–341.
Harrison, D G (2005) The Shear Stress of Keeping Arteries Clear. Nat Med 11: 375–376.
Heck, M and Hofmann, K P (2001) Maximal Rate and Nucleotide Dependence of Rhodopsin-Catalyzed Transducin Activation: Initial Rate Analysis Based on a Double Displacement Mechanism. J Biol Chem 276: 10000–10009.
Hein, P, Frank, M, Hoffmann, C, Lohse, M J and Bunemann, M (2005) Dynamics of Receptor/G-protein Coupling in Living Cells. EMBO J 24: 4106–4114.
Hishikawa, K, Nakaki, T, Marumo, T, Hayashi, M, Suzuki, H, Kato, R and Saruta, T (1994) Pressure Promotes DNA-Synthesis in Rat Cultured Vascular Smooth-Muscle Cells. J Clinical Investigation 93: 1975–1980.
Hoffmann, C, Gaietta, G, Bunemann, M, Adams, S R, Oberdorff-Maass, S, Behr, B, Vilardaga, J P, Tsien, R Y, Eisman, M H and Lohse, M J (2005) A FlAsH-Based FRET Approach to Determine G-protein – Coupled Receptor Activation in Living Cells. Nature Methods 2: 171–176.
Hsieh, H J, Li, N Q and Frangos, J A (1993) Pulsatile and Steady Flow Induces C-Fos Expression in Human Endothelial-Cells. J Physiol 154: 143–151.
Hsieh, H J, Li, N Q and Frangos, J A (1992) Shear-Induced Platelet-Derived Growth Factor Gene Expression in Human Endothelial Cells Is Mediated by Protein Kinase C. J Cell Physiol 150: 552–558.
Hunyady, L and Turu, G (2004) The Role of the AT1 Angiotensin Receptor in Cardiac Hypertrophy: Angiotensin II Receptor or Stretch Sensor?Trends Endocrinol Metab 15: 405–408.
Hutterer, R, Parusel, A B J and Hof, M (1998) Solvent Relaxation of Prodan and Patman: A Useful Tool for the Determination of Polarity and Rigidity Changes in Membranes. J Fluorescence 8: 389–393.
Ingber, D E (1997) Tensegrity: The Architectural Basis of Cellular Mechanotransduction. Ann Rev Physiol 59: 575–599.
Ishida, T, Takahashi, M, Corson, M A and Berk, B C (1997) Fluid Shear Stress-Mediated Signal Transduction: How Do Endothelial Cells Transduce Mechanical Force into Biological Responses?Ann NY Acad Sci 811: 12–23.
Ito, T, Yamazaki, M and Ohnishi, S (1989) Osmoelastic Coupling in Biological Structures – A Comprehensive Thermodynamic Analysis of the Osmotic Response of Phospholipid-Vesicles and a Reevaluation of the Dehydration Force Theory. Biochemistry 28: 5626–5630.
Jahnig, F (1996) What Is the Surface Tension of a Lipid Bilayer Membrane?Biophys J 71: 1348–1349.
Janetopoulos, C and Devreotes, P (2002) Monitoring Receptor-Mediated Activation of Heterotrimeric G-Proteins by Fluorescence Resonance Energy Transfer. Methods 27: 366–373.
Janiak, M J, Small, D M and Shipley, G G (1976) Nature of Thermal Pre-Transition of Synthetic Phospholipids – Dimyristoyllecithin and Dipalmitoyllecithin. Biochemistry 15: 4575–4580.
Jendrasiak, G L (1996) The Hydration of Phospholipids and Its Biological Significance. J Nutritional Biochem 7: 599–609.
Jin, Z G, Wong, C, Wu, J and Berk, B C (2005) Flow Shear Stress Stimulates Gab1 Tyrosine Phosphorylation to Mediate Protein Kinase B and Endothelial Nitric-Oxide Synthase Activation in Endothelial Cells. J Biol Chem 280: 12305–12309.
Jo, H, Sipos, K, Go, Y M, Law, R, Rong, J and McDonald, J M (1997) Differential Effect of Shear Stress on Extracellular Signal-Regulated Kinase and N-Terminal Jun Kinase in Endothelial Cells. Gi2- and Gbeta/Gamma-Dependent Signaling Pathways. J Biol Chem 272: 1395–1401.
Johannsson, A, Keightley, C A, Smith, G A, Richards, C D, Hesketh, T R and Metcalfe, J C (1981a) The Effect of Bilayer Thickness and Normal-Alkanes on the Activity of the (Ca2++Mg2+)-Dependent Atpase of Sarcoplasmic-Reticulum. J Biolog Chem 256: 1643–1650.
Johannsson, A, Smith, G A and Metcalfe, J C (1981b) The Effect of Bilayer Thickness on the Activity of (Na+ + K+)-Atpase. Biochimica et Biophysica Acta 641: 416–421.
Ju, H, Venema, V J, Marrero, M B and Venema, R C (1998) Inhibitory Interactions of the Bradykinin B2 Receptor with Endothelial Nitric-Oxide Synthase. J Biol Chem 273: 24025–24029.
Kadohama, T, Akasaka, N, Nishimura, K, Hoshino, Y, Sasajima, T and Sumpio, B E (2006) P38 Mitogen-Activated Protein Kinase Activation in Endothelial Cell Is Implicated in Cell Alignment and Elongation Induced by Fluid Shear Stress. Endothelium 13: 43–50.
Kinnunen, P K J, Koiv, A, Lehtonen, J Y A, Rytomaa, M and Mustonen, P (1994) Lipid Dynamics and Peripheral Interactions of Proteins with Membrane Surfaces. Chem Phys Lipids 73: 181–207.
Knudsen, H L and Frangos, J A (1997) Role of Cytoskeleton in Shear Stress-Induced Endothelial Nitric Oxide Production. Amer J Physiol – Heart and Circul Phys 42: H347–H355.
Komuro, I (2000) Molecular Mechanism of Mechanical Stress-Induced Cardiac Hypertrophy. Jpn Heart J 41: 117–129.
Korlach, J, Schwille, P, Webb, W W and Feigenson, G W (1999) Characterization of Lipid Bilayer Phases by Confocal Microscopy and Fluorescence Correlation Spectroscopy. Proceedings of the National Academy of Sciences of the United States of America 96: 8461–8466.
Krasnowska, E K, Gratton, E and Parasassi, T (1998) Prodan as a Membrane Surface Fluorescence Probe: Partitioning Between Water and Phospholipid Phases. Biophys J 74: 1984–1993.
Krichevsky, O and Bonnet, G (2002) Fluorescence Correlation Spectroscopy: The Technique and Its Applications. Reports on Progress in Physics 65: 251–297.
Krol, A Y, Grinfeldt, M G, Levin, S V and Smilgavichus, A D (1990) Local Mechanical Oscillations of the Cell-Surface Within the Range 0.2–30 Hz. European Biophys J 19: 93–99.
Ku, D N, Giddens, D P, Zarins, C K and Glagov, S (1985) Pulsatile Flow and Atherosclerosis in the Human Carotid Bifurcation. Positive Correlation Between Plaque Location and Low Oscillating Shear Stress. Arteriosclerosis 5: 293–302.
Kuchan, M J and Frangos, J A (1993) Shear Stress Regulates Endothelin-1 Release via Protein Kinase C and CGMP in Cultured Endothelial Cells. Am J Physiol 264: H150–H156.
Kuchan, M J, Jo, H and Frangos, J A (1994) Role of G-Proteins in Shear Stress-Mediated Nitric-Oxide Production by Endothelial-Cells. Am J Physiol 267: C753–C758.
Kung, C E and Reed, J K (1986) Microviscosity Measurements of Phospholipid-Bilayers Using Fluorescent Dyes That Undergo Torsional Relaxation. Biochemistry 25: 6114–6121.
Law, K Y (1980) Fluorescence Probe for Micro-Environments – Anomalous Viscosity Dependence of the Fluorescence Quantum Yield of Para-N,N-Dialkylaminobenzylidenemalononitrile in 1-Alkanols. Chem Phys Lett 75: 545–549.
Lee, A G (1998) How Lipids Interact with an Intrinsic Membrane Protein: The Case of the Calcium Pump. Biochim Biophys Acta 1376: 381–390.
Lee, A G (2004) How Lipids Affect the Activities of Integral Membrane Proteins. Biochim Biophys Acta 1666: 62–87.
Leeb-Lundberg, L M F, Marceau, F, Muller-Esterl, W, Pettibone, D J and Zuraw, B L (2005) International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: From Molecular Mechanisms to Pathophysiological Consequences. Pharmacol Rev 57: 27–77.
Lefkowitz, R J, Cotecchia, S, Samama, P and Costa, T (1993) Constitutive Activity of Receptors Coupled to Guanine-Nucleotide Regulatory Proteins. Trends Pharmacol Sci 14: 303–307.
Lehoux, S, Castier, Y and Tedgui, A (2006) Molecular Mechanisms of the Vascular Responses to Haemodynamic Forces. J Internal Med 259: 381–392.
Lehtonen, J Y A and Kinnunen, P K J (1994) Changes in the Lipid Dynamics of Liposomal Membranes Induced by Poly (Ethylene Glycol) – Free-Volume Alterations Revealed by Intermolecular and Intramolecular Excimer-Forming Phospholipid Analogs. Biophys J 66: 1981–1990.
Lehtonen, J Y A and Kinnunen, P K J (1995) Phospholipase A (2) as a Mechanosensor. Biophys J 68: 1888–1894.
Leurs, R, Smit, M J, Alewijnse, A E and Timmerman, H (1998) Agonist-Independent Regulation of Constitutively Active G-Protein-Coupled Receptors. Trends Biochem Sci 23: 418–422.
Levin, S and Korenstein, R (1991) Membrane Fluctuations in Erythrocytes Are Linked to Mgatp-Dependent Dynamic Assembly of the Membrane Skeleton. Biophys J 60: 733–737.
Liedtke, W, Tobin, D M, Bargmann, C I and Friedman, J M (2003) Mammalian TRPV4 (VR-OAC) Directs Behavioral Responses to Osmotic and Mechanical Stimuli in Caenorhabditis Elegans. Proceedings of the National Academy of Sciences of the United States of America 100: 14531–14536.
Litman, B J and Mitchell, D C (1996) A Role for Phospholipid Polyunsaturation in Modulating Membrane Protein Function. Lipids 31: S193–S197.
Loutfy, R O (1986) Fluorescence Probes for Polymer Free-Volume. Pure Appl Chem 58: 1239–1248.
Loutfy, R O and Law, K Y (1980) Electrochemistry and Spectroscopy of Intramolecular Charge-Transfer Complexes – Para-N,N-Dialkylaminobenzylidenemalononitriles. J Phys Chem 84: 2803–2808.
Luzardo, M D, Amalfa, F, Nunez, A M, Diaz, S, de Lopez, A C B and Disalvo, E A (2000) Effect of Trehalose and Sucrose on the Hydration and Dipole Potential of Lipid Bilayers. Biophys J 78: 2452–2458.
Makino, A, Glogauer, M, Bokoch, G M, Chien, S and Schmid-Schonbein, G W (2005) Control of Neutrophil Pseudopods by Fluid Shear: Role of Rho Family GTPases. Am J Phys – Cell Physiol 288: C863–C871.
Makino, A, Prossnitz, E R, Bunemann, M, Wang, J M, Yao, W and Schmid-Schonbein, G W (2006) G-protein-Coupled Receptors Serve as Mechanosensors for Fluid Shear Stress in Neutrophils. Am J Physiol – Cell Physiol 290: C1633–C1639.
Malek, A M, Alper, S L and Izumo, S (1999a) Hemodynamic Shear Stress and Its Role in Atherosclerosis. JAMA 282: 2035–2042.
Malek, A M, Jiang, L, Lee, I, Sessa, W C, Izumo, S and Alper, S L (1999b) Induction of Nitric Oxide Synthase MRNA by Shear Stress Requires Intracellular Calcium and G-Protein Signals and Is Modulated by PI 3 Kinase. Biochem Biophys Res Commun 254: 231–242.
Maroto, R, Raso, A, Wood, T G, Kurosky, A, Martinac, B and Hamill, O P (2005) TRPC1 Forms the Stretch-Activated Cation Channel in Vertebrate Cells. Nature Cell Biol 7: 179–U99.
Marrero, M B, Venema, V J, Ju, H, He, H, Liang, H Y, Caldwell, R B and Venema, R C (1999) Endothelial Nitric Oxide Synthase Interactions With G-Protein-Coupled Receptors. Biochem J 343: 335–340.
Martinac, B and Hamill, O P (2002) Gramicidin A Channels Switch Between Stretch Activation and Stretch Inactivation Depending on Bilayer Thickness. Proceedings of the National Academy of Sciences of the United States of America 99: 4308–4312.
Matsumoto, H, Baron, C B and Coburn, R F (1995) Smooth-Muscle Stretch-Activated Phospholipase-C Activity. Am J Physiol – Cell Physiol 37: C458–C465.
McAllister, T N and Frangos, J A (1999) Steady and Transient Fluid Shear Stress Stimulate NO Release in Osteoblasts Through Distinct Biochemical Pathways. J Bone Miner Res 14: 930–936.
Mccown, J T, Evans, E, Diehl, S and Wiles, H C (1981) Degree of Hydration and Lateral Diffusion in Phospholipid Multibilayers. Biochemistry 20: 3134–3138.
McMahon, H T and Gallop, J L (2005) Membrane Curvature and Mechanisms of Dynamic Cell Membrane Remodelling. Nature 438: 590–596.
Mitchell, D C, Straume, M and Litman, B J (1992) Role of Sn-1-Saturated,Sn-2-Polyunsaturated Phospholipids in Control of Membrane-Receptor Conformational Equilibrium – Effects of Cholesterol and Acyl Chain Unsaturation on the Metarhodopsin-I-Metarhodopsin-Ii Equilibrium. Biochemistry 31: 662–670.
Mittelman, L, Levin, S, Verschueren, H, Debaetselier, P and Korenstein, R (1994) Direct Correlation Between Cell-Membrane Fluctuations, Cell Filterability and the Metastatic Potential of Lymphoid-Cell Lines. Biochem Biophys Res Commun 203: 899–906.
Montecucco, C, Smith, G A, Dabbenisala, F, Johannsson, A, Galante, Y M and Bisson, R (1982) Bilayer Thickness and Enzymatic-Activity in the Mitochondrial Cytochrome C-Oxidase and Atpase Complex. FEBS Letters 144: 145–148.
Morris, A J and Malbon, C C (1999) Physiological Regulation of G-protein-Linked Signaling. Physiolog Rev 79: 1373–1430.
Mouritsen, O G and Bloom, M (1993) Models of Lipid-Protein Interactions in Membranes. Ann Rev Biophys Biomolec Structure 22: 145–171.
Muller, H J and Galla, H J (1983) Pressure Variation of the Lateral Diffusion in Lipid Bilayer-Membranes. Biochimica et Biophysica Acta 733: 291–294.
Munro, S (2003) Lipid Rafts: Elusive or Illusive?Cell 115: 377–388.
Nagle, J F (1980) Theory of the Main Lipid Bilayer Phase-Transition. Ann Rev Phys Chem 31: 157–195.
Naka, K, Sadownik, A and Regen, S L (1992) Molecular Harpoons – Membrane-Disrupting Surfactants That Recognize Osmotic-Stress. J Am Chem Soc 114: 4011–4013.
Nakamura, F and Strittmatter, S M (1996) P2Y (1) Purinergic Receptors in Sensory Neurons: Contribution to Touch-Induced Impulse Generation. Proceedings of the National Academy of Sciences of the United States of America 93: 10465–10470.
Needham, D and Nunn, R S (1990) Elastic-Deformation and Failure of Lipid Bilayer-Membranes Containing Cholesterol. Biophys J 58: 997–1009.
Nerem, R M (1992) Vascular Fluid Mechanics, the Arterial Wall, and Atherosclerosis. J Biomech Eng 114: 274–282.
Novikov, E G and Visser, A J W G (2001) Inter- and Intramolecular Dynamics of Pyrenyl Lipids in Bilayer Membranes from Time-Resolved Fluorescence Spectroscopy. J Fluorescence 11: 297–305.
Ohno, M, Gibbons, G H, Dzau, V J and Cooke, J P (1993) Shear Stress Elevates Endothelial CGMP. Role of a Potassium Channel and G-protein Coupling. Circulation 88: 193–197.
Okada, T, Ernst, O P, Palczewski, K and Hofmann, K P (2001) Activation of Rhodopsin: New Insights from Structural and Biochemical Studies. Trends in Biochem Sci 26: 318–324.
Oldham, W M and Hamm, H E (2006) Structural Basis of Function in Heterotrimeric G-proteins 28. Q Rev Biophys 39: 117–166.
Oldham, W M, Van, E N, Preininger, A M, Hubbell, W L and Hamm, H E (2006) Mechanism of the Receptor-Catalyzed Activation of Heterotrimeric G-proteins 30. Nat Struct Mol Biol 13: 772–777.
Paoletti, P and Ascher, P (1994) Mechanosensitivity of Nmda Receptors in Cultured Mouse Central Neurons. Neuron 13: 645–655.
Parasassi, T, Destasio, G, Dubaldo, A, Rusch, R and Gratton, E (1990) Phase Fluctuation in Phospholipids Revealed by Laurdan Fluorescence. Biophys J 57: A272.
Parasassi, T, Destasio, G, Ravagnan, G, Rusch, R M and Gratton, E (1991) Quantitation of Lipid Phases in Phospholipid-Vesicles by the Generalized Polarization of Laurdan Fluorescence. Biophys J 60: 179–189.
Parasassi, T, Krasnowska, E K, Bagatolli, L and Gratton, E (1998) LAURDAN and PRODAN as Polarity-Sensitive Fluorescent Membrane Probes. J Fluorescence 8: 365–373.
Parasassi, T, Loiero, M, Raimondi, M, Ravagnan, G and Gratton, E (1993) Absence of Lipid Gel-Phase Domains in Seven Mammalian Cell Lines and in Four Primary Cell Types. Biochim Biophys Acta 1153: 143–154.
Parola, A H (1993) in Biomembranes Physical Aspects (Shinitsky, M, ed.), pp. 159–277, VCH, New York.
Parsegian, V A, Rand, R P and Rau, D C (2000) Osmotic Stress, Crowding, Preferential Hydration, and Binding: A Comparison of Perspectives. Proceedings of the National Academy of Sciences of the United States of America 97: 3987–3992.
Patel, A J, Lazdunski, M and Honore, E (2001) Lipid and Mechano-Gated 2P Domain K+ Channels. Current Opinion in Cell Biology 13: 422–427.
Peleg, G, Ghanouni, P, Kobilka, B K and Zare, R N (2001) Single-Molecule Spectroscopy of the Beta (2) Adrenergic Receptor: Observation of Conformational Substates in a Membrane Protein. Proceedings of the National Academy of Sciences of the United States of America 98: 8469–8474.
Perez, D M and Karnik, S S (2005) Multiple Signaling States of G-Protein-Coupled Receptors. Pharmacol Rev 57: 147–161.
Perozo, E, Cortes, D M, Sompornpisut, P, Kloda, A and Martinac, B (2002a) Open Channel Structure of MscL and the Gating Mechanism of Mechanosensitive Channels. Nature 418: 942–948.
Perozo, E, Kloda, A, Cortes, D M and Martinac, B (2002b) Physical Principles Underlying the Transduction of Bilayer Deformation Forces During Mechanosensitive Channel Gating. Nature Structural Biology 9: 696–703.
Peters, R and Cherry, R J (1982) Lateral and Rotational Diffusion of Bacteriorhodopsin in Lipid Bilayers – Experimental Test of the Saffman-Delbruck Equations. Proceedings of the National Academy of Sciences of the United States of America – Biological Sciences 79: 4317–4321.
Pi, X, Yan, C and Berk, B C (2004) Big Mitogen-Activated Protein Kinase (BMK1)/ERK5 Protects Endothelial Cells from Apoptosis. Circ Res 94: 362–369.
Polozova, A and Litman, B J (2000) Cholesterol Dependent Recruitment of Di22: 6-PC by a G-protein-Coupled Receptor into Lateral Domains. Biophys J 79: 2632–2643.
Rand, R P, Parsegian, V A and Rau, D C (2000) Intracellular Osmotic Action. Cellular and Molecular Life Sciences 57: 1018–1032.
Reich, K M, Mcallister, T N, Gudi, S and Frangos, J A (1997) Activation of G-proteins Mediates Flow-Induced Prostaglandin E (2) Production in Osteoblasts. Endocrinology 138: 1014–1018.
Rietveld, A, Neutz, S, Simons, K and Eaton, S (1999) Association of Sterol- and Glycosylphosphatidylinositol-Linked Proteins with Drosophila Raft Lipid Microdomains. J Biol Chem 274: 12049–12054.
Rigler, R and Elson, ES (2001) Fluorescence Correlation Spectroscopy. Springer, Berlin.
Rizzo, V, McIntosh, D P, Oh, P and Schnitzer, J E (1998) In Situ Flow Activates Endothelial Nitric Oxide Synthase in Luminal Caveolae of Endothelium with Rapid Caveolin Dissociation and Calmodulin Association. J Biol Chem 273: 34724–34729.
Rizzo, V, Morton, C, DePaola, N, Schnitzer, J E and Davies, P F (2003) Recruitment of Endothelial Caveolae into Mechanotransduction Pathways by Flow Conditioning in Vitro. Am J Physiol – Heart and Circulatory Physiol 285: H1720–H1729.
Roberts, D J and Waelbroeck, M (2004) G-protein Activation by G-protein Coupled Receptors: Ternary Complex Formation or Catalyzed Reaction?Biochem Pharmacol 68: 799–806.
Sackin, H (1995) Mechanosensitive Channels. Ann Rev Physiol 57: 333–353.
Saffman, P G and Delbruck, M (1975) Brownian-Motion in Biological Membranes. Proceedings of the National Academy of Sciences of the United States of America 72: 3111–3113.
Safran, A S (2003) Statistical Thermodynamics of Surfaces, Interfaces and Membranes. Westview Press, Boulder, Co.
Salwen, S A, Szarowski, D H, Turner, J N and Bizios, R (1998) Three-Dimensional Changes of the Cytoskeleton of Vascular Endothelial Cells Exposed to Sustained Hydrostatic Pressure. Medical & Biological Engineering & Computing 36: 520–527.
Schwartz, E A, Bizios, R, Medow, M S and Gerritsen, M E (1999) Exposure of Human Vascular Endothelial Cells to Sustained Hydrostatic Pressure Stimulates Proliferation – Involvement of the Alpha (v) Integrins. Circ Res 84: 315–322.
Schwarz, G, Callewaert, G, Droogmans, G and Nilius, B (1992) Shear Stress-Induced Calcium Transients in Endothelial Cells from Human Umbilical Cord Veins. J Physiol 458: 527–538.
Sessa, W C (2004) ENOS at a Glance. J Cell Sci 117: 2427–2429.
Simon, S A and Mcintosh, T J (1986) Depth of Water Penetration into Lipid Bilayers. Methods in Enzymology 127: 511–521.
Simons, K and Toomre, D (2000) Lipid Rafts and Signal Transduction. Nature Rev Mol Cell Biol 1: 31–39.
Simons, K and Vaz, W L C (2004) Model Systems, Lipid Rafts, and Cell Membranes. Ann Rev Biophys Biomolec Structure 33: 269–295.
Soderlund, T, Alakoskela, J M I, Pakkanen, A L and Kinnunen, P K J (2003) Comparison of the Effects of Surface Tension and Osmotic Pressure on the Interfacial Hydration of a Fluid Phospholipid Bilayer. Biophys J 85: 2333–2341.
Sukharev, S I, Blount, P, Martinac, B, Blattner, F R and Kung, C (1994) A Large-Conductance Mechanosensitive Channel in E. Coli Encoded by Mscl Alone. Nature 368: 265–268.
Sumpio, B E, Yun, S, Cordova, A C, Haga, M, Zhang, J, Koh, Y and Madri, J A (2005) MAPKs (ERK1/2, P38) and AKT Can Be Phosphorylated by Shear Stress Independently of Platelet Endothelial Cell Adhesion Molecule-1 (CD31) in Vascular Endothelial Cells 45. J Biol Chem 280: 11185–11191.
Surapisitchat, J, Hoefen, R J, Pi, X, Yoshizumi, M, Yan, C and Berk, B C (2001) Fluid Shear Stress Inhibits TNF-Alpha Activation of JNK but Not ERK1/2 or P38 in Human Umbilical Vein Endothelial Cells: Inhibitory Crosstalk Among MAPK Family Members. Proceedings of the National Academy of Sciences of the United States America 98: 6476–6481.
Svindland, A (1983) The Localization of Sudanophilic and Fibrous Plaques in the Main Left Coronary Bifurcation. Atherosclerosis 48: 139–145.
Takahashi, M, Ishida, T, Traub, O, Corson, M A and Berk, B C (1997) Mechanotransduction in Endothelial Cells: Temporal Signaling Events in Response to Shear Stress. J Vasc Res 34: 212–219.
Traub, O and Berk, B C (1998) Laminar Shear Stress: Mechanisms by Which Endothelial Cells Transduce an Atheroprotective Force. Arterioscler Thromb Vasc Biol 18: 677–685.
Traub, O, Monia, B P, Dean, N M and Berk, B C (1997) PKC-Epsilon Is Required for Mechano-Sensitive Activation of ERK1/2 in Endothelial Cells. J Biol Chem 272: 31251–31257.
Tseng, H, Peterson, T E and Berk, B C (1995) Fluid Shear Stress Stimulates Mitogen-Activated Protein Kinase in Endothelial Cells. Circ Res 77: 869–878.
Tuvia, S, Almagor, A, Bitler, A, Levin, S, Korenstein, R and Yedgar, S (1997) Cell Membrane Fluctuations Are Regulated by Medium Macroviscosity: Evidence for a Metabolic Driving Force. Proceedings of the National Academy of Sciences of the United States of America 94: 5045–5049.
Tuvia, S, Levin, S, Bitler, A and Korenstein, R (1998) Mechanical Fluctuations of the Membrane-Skeleton Are Dependent on F-Actin ATPase in Human Erythrocytes. J Cell Biol 141: 1551–1561.
Tzima, E, Irani-Tehrani, M, Kiosses, W B, Dejana, E, Schultz, D A, Engelhardt, B, Cao, G, DeLisser, H and Schwartz, M A (2005) A Mechanosensory Complex That Mediates the Endothelial Cell Response to Fluid Shear Stress. Nature 437: 426–431.
Vaz, W L C, Clegg, R M and Hallmann, D (1985) Translational Diffusion of Lipids in Liquid-Crystalline Phase Phosphatidylcholine Multibilayers – A Comparison of Experiment with Theory. Biochemistry 24: 781–786.
Vaz, W L C, Goodsaidzalduondo, F and Jacobson, K (1984) Lateral Diffusion of Lipids and Proteins in Bilayer-Membranes. FEBS Letters 174: 199–207.
Viard, M, Gallay, J, Vincent, M, Meyer, O, Robert, B and Paternostre, M (1997) Laurdan Solvatochromism: Solvent Dielectric Relaxation and Intramolecular Excited-State Reaction. Biophys J 73: 2221–2234.
Vilardaga, J P, Bunemann, M, Krasel, C, Castro, M and Lohse, M J (2003) Measurement of the Millisecond Activation Switch of G-protein-Coupled Receptors in Living Cells. Nature Biotechnol 21: 807–812.
Vilardaga, J P, Steinmeyer, R, Harms, G S and Lohse, M J (2005) Molecular Basis of Inverse Agonism in a G-protein-Coupled Receptor. Nature Chemical Biol 1: 25–28.
Vogler, O, Casas, J, Capo, D, Nagy, T, Borchert, G, Martorell, G and Escriba, P V (2004) The G Beta Gamma Dimer Drives the Interaction of Heterotrimeric G (i) Proteins with Nonlamellar Membrane Structures. J Biol Chem 279: 36540–36545.
Wang, X L, Fu, A, Raghavakaimal, S and Lee, H C (2007) Proteomic Analysis of Vascular Endothelial Cells in Response to Laminar Shear Stress. Proteomics 7: 588–596.
Wang, Y, Botelho, A V, Martinez, G V and Brown, M F (2002) Electrostatic Properties of Membrane Lipids Coupled to Metarhodopsin II Formation in Visual Transduction. J Am Chem Soci 124: 7690–7701.
Wedgwood, S, Bekker, J M and Black, S M (2001) Shear Stress Regulation of Endothelial NOS in Fetal Pulmonary Arterial Endothelial Cells Involves PKC. Am J Physiol Lung Cell Mol Physiol 281: L490–L498.
Werry, T D, Sexton, P M and Christopoulos, A (2005) “Ins and Outs” of Seven-Transmembrane Receptor Signalling to ERK. Trends in Endocrinology and Metabolism 16: 26–33.
White, C R, Dusserre, N and Frangos, J A (2003) Steady and Unsteady Fluid Shear Control of Inflammation, in Molecular Basis of Microcirculatory Disorders (Schmid-Schoenbein, G W and Granger, N D, eds.), pp. 141–160, Springer-Verlag, New York.
White, C R and Frangos, J A (2007) The Shear Stress of It All: The Cell Membrane and Mechanochemical Transduction. Philos Trans R Soc Lond B Biol Sci.
White, C R, Stevens, H Y, Haidekker, M and Frangos, J A (2005) Temporal Gradients in Shear, but Not Spatial Gradients, Stimulate ERK1/2 Activation in Human Endothelial Cells. Am J Physiol – Heart Circ Physiol 289: H2350–H2355.
Wiggins, P and Phillips, R (2004) Analytic Models for Mechanotransduction: Gating a Mechanosensitive Channel. Proceedings of the National Academy of Sciences of the United States of America 101: 4071–4076.
Yamazaki, M, Ohnishi, S and Ito, T (1989) Osmoelastic Coupling in Biological Structures – Decrease in Membrane Fluidity and Osmophobic Association of Phospholipid-Vesicles in Response to Osmotic-Stress. Biochemistry 28: 3710–3715.
Yamazaki, T, Komuro, I, Shiojima, I and Yazaki, Y (1999) The Molecular Mechanism of Cardiac Hypertrophy and Failure. Ann NY Acad Sci 874: 38–48.
Yang, Q, Alemany, R, Casas, J, Kitajka, K, Lanier, S M and Escriba, P V (2005) Influence of the Membrane Lipid Structure on Signal Processing via G-protein-Coupled Receptors. Molecular Pharmacology 68: 210–217.
Yu, J, Bergaya, S, Murata, T, Alp, I F, Bauer, M P, Lin, M I, Drab, M, Kurzchalia, T V, Stan, R V and Sessa, W C (2006) Direct Evidence for the Role of Caveolin-1 and Caveolae in Mechanotransduction and Remodeling of Blood Vessels. J Clin Investig 116: 1284–1291.
Zhang, Y L, Frangos, J A and Chachisvilis, M (2006) Laurdan Fluorescence Senses Mechanical Strain in the Lipid Bilayer Membrane. Biochem Biophys Res Communic 347: 838–841.
Zou, Y Z, Akazawa, H, Qin, Y J, Sano, M, Takano, H, Minamino, T, Makita, N, Iwanaga, K, Zhu, W D, Kudoh, S, Toko, H, Tamura, K, Kihara, M, Nagai, T, Fukamizu, A, Umemura, S, Iiri, T, Fujita, T and Komuro, I (2004) Mechanical Stress Activates Angiotensin II Type 1 Receptor Without the Involvement of Angiotensin II. Nature Cell Biology 6: 499–506.