Spin label study of local anesthetic-lipid membrane interactions. Phase separation of the uncharged from and bilayer micellization by the charged form of tetracaine

Frezzatti, Wilson A.; Toselli, W R; Schreier, Shirley

doi:10.1016/0005-2736(86)90550-x

Cited by 42 publications

(12 citation statements)

References 31 publications

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“…As confirmation, the inward movement of phosphatidylcholine and sphingomyelin has been measured upon intercalation of cationic amphiphiles into the erythrocyte membrane (Schrier et al, 1992). Arguments pointing to a membrane bilayer destabilization for tetracaine and propranolol include: (i) formation of mixed tetracaine-phosphatidylcholine micelles in egg phosphatidylcholine bilayers (Frezzatti et al, 1986) and propranolol-induced increase in membrane fluidity (Shi & Tien, 1986), (ii) displacement of Ca 2þ from the cytoplasmic face of the erythrocyte membrane by increasing the distance between adjacent protein and/ or phospholipid components of a Ca 2þ attachment site (Low et al, 1979), and (iii) drug-binding to aminophospholipids, thus destabilizing the original membrane phospholipid organization (Keluski et al, 1986;DacharyPrigent et al, 1979). These data can account for a transbilayer movement of phospholipids by a high drug to lipid ratio associated with the Ca 2þ -induced inhibition of aminophospholipid translocase activity in platelets.…”

Section: Discussionmentioning

confidence: 99%

Aminophospholipid exposure, microvesiculation and abnormal protein tyrosine phosphorylation in the platelets of a patient with Scott syndrome: a study using physiologic agonists and local anaesthetics

et al. 1997

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Summary. The Scott syndrome is a rare inherited haemorrhagic disorder characterized by the inability of blood cells to expose aminophospholipids and to shed microparticles. We have had the opportunity to study a recently reported French patient with this syndrome and have confirmed by means of a fluorescence assay for transbilayer lipid movement a reduced aminophospholipid exposure when platelets were stimulated with the calcium-ionophore ionomycin, in spite of a normal elevation of intracellular Ca 2þ . Secretion and calpain activation were also shown to be normal. Significantly, the level of phosphotyrosine-labelled proteins in platelets treated with thrombin or a thrombin þ collagen mixture and in particular the phosphorylation of a 40 kD band were severely reduced. Furthermore, inhibition of thiolcontaining enzymes, including tyrosine-phosphatases, by Nethyl maleimide did not lead to aminophospholipid exposure in the patient's platelets, in spite of increased tyrosine protein phosphorylation. In contrast, amphiphilic membrane drugs such as tetracaine and propranolol induced both surface aminophospholipid exposure in Scott platelets and the shedding of microparticles, thereby showing that membrane perturbation can lead to loss of phospholipid asymmetry in this syndrome. Our results provide the first insight that the lack of expression of procoagulant phospholipids and microparticle formation in Scott syndrome platelets is associated with a defect of intracellular signalling.

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Section: Discussionmentioning

confidence: 99%

Aminophospholipid exposure, microvesiculation and abnormal protein tyrosine phosphorylation in the platelets of a patient with Scott syndrome: a study using physiologic agonists and local anaesthetics

et al. 1997

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“…The wish to understand the molecular mechanisms by which local anesthetics block different types of ion channels (8,9) and the mechanisms by which irreversible nerve injury is caused by local anesthetics (10) has driven the study of local anesthetic-membrane interactions for over three decades. The dynamics of drug:membrane interactions have been investigated previously by others using a variety of physical methods, including x-ray diffraction (11,12), NMR (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), electron paramagnetic resonance (28)(29)(30)(31)(32)(33), and Fourier transform infrared spectroscopy (24,(34)(35)(36)(37)(38). These methods, although providing good spatial resolution, are very slow and cannot resolve any kinetic processes in this interaction.…”

Section: Introductionmentioning

confidence: 99%

“…For example, charged tetracaine may form micelles (29,41), for which it has a different behavior than as monomers in solution, and also can dissolve membranes through its detergent action. As a consequence of the second property, at high concentrations tetracaine may induce significant changes in membrane structure and phase-transition parameters, even forming tetracainelipid mixed micelles (23,29,(41)(42)(43)(44). Additionally, tetracaine at high concentration can form dimers, at least in the membrane (26).…”

Section: Introductionmentioning

confidence: 99%

Tetracaine-Membrane Interactions: Effects of Lipid Composition and Phase on Drug Partitioning, Location, and Ionization

Zhang

Hadlock

Gent

et al. 2007

Biophysical Journal

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Interactions of the local anesthetic tetracaine with unilamellar vesicles made of dimyristoyl or dipalmitoyl phosphatidylcholine (DMPC or DPPC), the latter without or with cholesterol, were examined by following changes in the drug's fluorescent properties. Tetracaine's location within the membrane (as indicated by the equivalent dielectric constant around the aromatic fluorophore), its membrane:buffer partition coefficients for protonated and base forms, and its apparent pK(a) when adsorbed to the membrane were determined by measuring, respectively, the saturating blue shifts of fluorescence emission at high lipid:tetracaine, the corresponding increases in fluorescence intensity at this lower wavelength with increasing lipid, and the dependence of fluorescence intensity of membrane-bound tetracaine (TTC) on solution pH. Results show that partition coefficients were greater for liquid-crystalline than solid-gel phase membranes, whether the phase was set by temperature or lipid composition, and were decreased by cholesterol; neutral TTC partitioned into membranes more strongly than the protonated species (TTCH(+)). Tetracaine's location in the membrane placed the drug's tertiary amine near the phosphate of the headgroup, its ester bond in the region of the lipids' ester bonds, and associated dipole field and the aromatic moiety near fatty acyl carbons 2-5; importantly, this location was unaffected by cholesterol and was the same for neutral and protonated tetracaine, showing that the dipole-dipole and hydrophobic interactions are the critical determinants of tetracaine's location. Tetracaine's effective pK(a) was reduced by 0.3-0.4 pH units from the solution pK(a) upon adsorption to these neutral bilayers, regardless of physical state or composition. We propose that the partitioning of tetracaine into solid-gel membranes is determined primarily by its steric accommodation between lipids, whereas in the liquid-crystalline membrane, in which the distance between lipid molecules is larger and steric hindrance is less important, hydrophobic and ionic interactions between tetracaine and lipid molecules predominate.

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“…Local anesthetic-membrane interaction has been a theme of research in our laboratory (34,35). Here we present work on the binding of the protonated and neutral forms of the local anesthetic tetracaine (TTC) to zwitterionic micelles of N-hexadecyl-N,N-dimethyl-3-ammonium-1 -propanesulfonate (HPS) and egg lysophosphatidyl choline (LPC) and on the effect of ions (sulfate, chloride, thiocyanate and perchlorate) and urea on the extent of binding of both forms.…”

Section: Introductionmentioning

confidence: 99%

Effect of Anions from the Hofmeister Series and Urea on the Binding of the Charged and Uncharged Forms of the Local Anesthetic Tetracaine to Zwitterionic Micelles*

Ferreira¹,

Périgo²,

Politi³

et al. 1996

Photochem & Photobiology

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It is widely known that ions in the aqueous phase affect the binding of charged solutes to membranes. Here we report the effect of ions and urea on the interaction of both the charged and uncharged forms of the local anesthetic tetracaine (TTC, an aminoester derivative of benzoic acid) to zwitterionic micelles. Binding was monitored by the increase in TTC fluorescence. Shifts in the emission wavelength maximum (Lax) indicated that the anesthetic was located in an environment of lower polarity. The neutral form of TTC bound to micelles to a larger extent than the protonated form, in agreement with results found for lipid bilayers (Boulanger, Leitch, Schreier and Smith, Can. J. Biochem. 58, 986-995, 1980). When ions from the Hofmeister series and urea were compared in their ability to affect the partitioning of the anesthetic, binding of both the charged and uncharged forms was found to increase upon addition of S042and CI-but was seen to decrease in the presence of SCN-, C104-and urea. Solubility measurements revealed that the solubility of uncharged TTC increases in solutions containing the additives in the following order: S042-< C1-< C10,-< dilute buffer < SCN-< urea. Spin label EPR spectra indicated that, except for C104-, the ions had little effect on micellar structure. Static light scattering measurements corroborated this result indicating a large increase in micellar molecular weight in the presence of C104-and lesser increases for C1.-and SCN-. The results show that, besides affecting the binding of ionic species through an electrostatic mechanism, ions also act by altering water structure and, as a consequence, the water solubility and the tendency to partition into the less polar micellar environment of polar charged or uncharged small organic solutes such as the benzoic acid ester derivative. Moreover, evidence suggests that the ions bind directly to the zwitterionic polar groups of the micelles, leading to changes in structure and size.

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Spin label study of local anesthetic-lipid membrane interactions. Phase separation of the uncharged from and bilayer micellization by the charged form of tetracaine

Cited by 42 publications

References 31 publications

Aminophospholipid exposure, microvesiculation and abnormal protein tyrosine phosphorylation in the platelets of a patient with Scott syndrome: a study using physiologic agonists and local anaesthetics

Aminophospholipid exposure, microvesiculation and abnormal protein tyrosine phosphorylation in the platelets of a patient with Scott syndrome: a study using physiologic agonists and local anaesthetics

Tetracaine-Membrane Interactions: Effects of Lipid Composition and Phase on Drug Partitioning, Location, and Ionization

Effect of Anions from the Hofmeister Series and Urea on the Binding of the Charged and Uncharged Forms of the Local Anesthetic Tetracaine to Zwitterionic Micelles*

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