Abstract
The effects of local anesthetics (LAs), including aminoamides and aminoesters, on the characteristics of single gramicidin A (GA) channels in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayers were studied. Aminoamides, namely lidocaine (LDC), prilocaine (PLC), mepivacaine (MPV), and bupivacaine (BPV), reduced the conductance of GA channels. Aminoesters influenced the current fluctuations induced by GA differently; procaine (PC) did not affect the fluctuations, whereas tetracaine (TTC) distinctly reduced the conductance of single GA channels. Using electrophysiological technique, we estimated the changes in the membrane boundary potential at the adsorption of LAs; LDC, PLC, MPV, BPV, and TTC substantially increased, while PC did not affect it. To elucidate which component of the membrane boundary potential, the surface or dipole potential, is responsible for the observed effects of LAs, we employed a fluorescence assay. We found that TTC led to a significant increase in the membrane dipole potential, whereas the adsorption of LDC, PLC, MPV, BPV, and PC did not produce any changes in the membrane dipole potential. We concluded that aminoamides affected the surface potential of lipid bilayers. Together, these data suggest that the effects of LAs on the conductance of single GA channels are caused by their influence on membrane electrostatic potentials; the regulation of GA pores by aminoamides is associated with the surface potential of membranes, whereas TTC modulation of channel properties is predominantly due to changes in dipole potential of lipid bilayers. These data might provide some significant implications for voltage-gated ion channels of cell membranes.
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References
Andersen OS, Koeppe RE (1992) Molecular determinants of channel function. Physiol Rev 72:S89–158
Andersen OS, Finkelstein A, Katz I, Cass A (1976) Effect of phloretin on the permeability of thin lipid membranes. J Gen Physiol 67:749–771
Busath DD, Thulin CD, Hendershot RW, Phillips LR, Maughan P, Cole CD, Bingham NC, Morrison S, Baird LC, Hendershot RJ, Cotten M, Cross TA (1998) Noncontact dipole effects on channel permeation. I. Experiments with (5F-indole)Trp13 gramicidin A channels. Biophys J 75:2830–2844
Butterworth JF, Strichartz GR (1990) Molecular mechanisms of local anesthesia: a review. Anesthesiology 72:711–734
Cherny AV, Sokolov VS, Cherny VV (1993) The distribution of potential at the membrane/solution interface at the adsorption of tetracaine. Electrochem 29:364–368
Clarke RJ (1997) Effect of lipid structure on the dipole potential of phosphatidylcholine bilayers. Biochim Biophys Acta 1327:269–278
Clarke RJ, Kane DJ (1997) Optical detection of membrane dipole potential: avoidance of fluidity and dye-induced effects. Biochim Biophys Acta 1323:223–239
Cseh R, Benz R (1998) The adsorption of phloretin to lipid monolayers and bilayers cannot be explained by langmuir adsorption isotherms alone. Biophys J 74:1399–1408
Duffin RL, Garrett MP, Flake KB, Durrant JD, Busath DD (2003) Modulation of lipid bilayer interfacial dipole potential by phloretin, RH 421, and 6-ketocholestanol as probed by gramicidin channel conductance. Langmuir 19:1439–1442
Ermakov YuA, Sokolov VS (2003) Boundary potentials of bilayer lipid membranes: methods and interpretations. In: Tien HT, Ottova-Leitmannova A (eds) Planar Lipid Bilayers (BLMs) and their applications. Elsevier, New York, pp 109–141
Gawrisch K, Ruston D, Zimmerberg J, Parsegian VA, Rand RP, Fuller N (1992) Membrane dipole potentials, hydration forces, and the ordering of water at membrane surfaces. Biophys J 61:1213–1223
Gross E, Bedlack RS, Loew LM (1994) Dual-wavelength ratiometric fluorescence measurement of the membrane dipole potential. Biophys J 67:208–216
Hianik T, Fajkus M, Tarus B, Frangopol PT, Markin VS, Landers DF (1998) The electrostriction, surface potential and capacitance relaxation of bilayer lipid membranes induced by tetracaine. Bioelectrochem Bioenerg 46:1–5
Hille B (1977) Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69:497–515
Hogberg C-J, Lyubartsev AP (2008) Effect of local anesthetic lidocaine on electrostatic properties of a lipid bilayer. Biophys J 94:525–531
Maas AH, Rispens P, Siggaard-Andersen O, Zijlstra WG (1984) On the reliability of the Henderson-Hasselbalch equation in routine clinical acid-base chemistry. Ann Clin Biochem 21:26–39
Mojumdar EH, Lyubartsev AP (2010) Molecular dynamics simulations of local anesthetic articaine in a lipid bilayer. Biophys Chem 153:27–35
Montal M, Muller P (1972) Formation of bimolecular membranes from lipid monolayers and study of their electrical properties. Proc Nat Acad Sci USA 65:3561–3566
Nilius B, Benndorf K, Markwardt F (1987) Effects of lidocaine on single cardiac sodium-channels. J Mol Cell Cardiol 19:865–874
Paiva JG, Paradiso P, Serro AP, Fernandes A, Saramago B (2012) Interaction of local and general anaesthetics with liposomal membrane models: a QCM-D and DSC study. Colloids Surf B Biointerfaces 95:65–74
Ragdale DS, McPhee JC, Scheuer T, Catterall WA (1994) Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science 265:1724–1728
Rokitskaya TI, Antonenko YN, Kotova EA (1997) Effect of the dipole potential of a bilayer lipid membrane on gramicidin channel dissociation kinetics. Biophys J 73:850–854
Rostovtseva TK, Aguilella VM, Vodyanoy I, Bezrukov SM, Parsegian VA (1998) Membrane surface-charge titration probed by gramicidin a channel conductance. Biophys J 75:1783–1792
Shimooka T, Shibata A, Terada H (1992) The local anesthetic tetracaine destabilizes membrane structure by interaction with polar headgroups of phospholipids. Biochim Biophys Acta 1104:261–268
Starke-Peterkovic T, Turner N, Vitha MF, Waller MP, Hibbs DE, Clarke RJ (2006) Electric field strength of membrane lipids from vertebrate species: membrane lipid composition and Na+ -K+ -ATPase molecular activity. Biophys J 90:4060–4070
Strichartz GR, Sanchez V, Arthur GR, Chafetz R, Martin D (1990) Fundamental properties of local anesthetics. II. Measured octanol: buffer partition coefficients and pKa values of clinically used drugs. Anesth Analg 71:158–170
Tsuchiya H, Mizogami M (2013) Interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol: mechanistic and clinical implications for anesthetic and cardiotoxic effects. Anesthesiol Res Pract 2013:297141
Weiser T (2006) Comparison of the effect of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Mav 1.2 channels. Neurosci Lett 395:179–184
Acknowledgments
The authors thank Prof. Valery Malev for fruitful discussions and Roman Medvedev and Evgeny Chulkov for the technical assistance. This work was supported by the Russian Foundation for Basic Research (# 15-34-20356) (OSO, AAZ), SP-69.2015.4 (SSE), and the Program “Molecular and Cell Biology” of the Russian Academy of Sciences (LVS).
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Efimova, S.S., Zakharova, A.A., Schagina, L.V. et al. Local Anesthetics Affect Gramicidin A Channels via Membrane Electrostatic Potentials. J Membrane Biol 249, 781–787 (2016). https://doi.org/10.1007/s00232-016-9926-x
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DOI: https://doi.org/10.1007/s00232-016-9926-x