Interfacial ionization and partitioning of membrane-bound local anaesthetics

Miyazaki, Jinsei; Hideg, Kálmán; Marsh, Derek

doi:10.1016/0005-2736(92)90057-s

Cited by 100 publications

(67 citation statements)

References 20 publications

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“…Comparing the slices of the two-dimensional spectrum of phenylalanine methyl ester with those of the lipids indicates that the aromatic Phe side chain resides at the level of the choline head group. This is the predicted position if the N-terminal charge is anchored at the membrane-solution interface, a location expected from energetic considerations and prior work with the charged form of the simple fatty acids (43)(44)(45). This surface position is further supported by a strong cross-peak between the Phe ring protons and water at long mixing times.…”

Section: Penetration Of Aromatic Phenylalanine Rings Into Membranesupporting

confidence: 61%

Binding of Peptides with Basic and Aromatic Residues to Bilayer Membranes

Zhang

Crocker

McLaughlin

et al. 2003

Journal of Biological Chemistry

109

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Many peripheral membrane proteins contain unstructured clusters of basic and aromatic residues that interact with lipid bilayers. In some cases, these clusters can bind phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) 1 (Fig. 1C), a key regulator of signal transduction in cell membranes (for reviews, see Refs. 1-8). For instance, binding of PI(4,5)P 2 to the basic-aromatic cluster on phospholipase D activates the enzyme (9 -11), whereas a similar cluster in the effector domain (residues 151-175) of the myristoylated alanine-rich C kinase substrate (MARCKS) protein may act as a reversible buffer for regulating free PI(4,5)P 2 levels in the plasma membrane (2). Peptides corresponding to basic-aromatic clusters of phospholipase D and MARCKS bind PI(4,5)P 2 with high affinity and specificity compared with monovalent acid lipids such as phosphatidylserine (11-13). To establish how these clusters can bind to the membrane, selectively sequester PI(4,5)P 2 , and possibly exert other effects on membrane structure, we need to establish their specific location within the bilayer. This study focuses on the effector domain of the MARCKS protein, one of the major substrates for protein kinase C (for reviews, see Refs. 14 -16). MARCKS associates with membranes through an N-terminal myristoyl group and a cluster of basic-aromatic amino acids in its effector domain (16). The five Phe residues in the basic effector domain may influence membrane binding or structure in several different ways, depending on the degree to which they penetrate the membrane bilayer. For example, as we discuss in more detail below, they could (i) contribute a hydrophobic term to the membrane-binding energy, (ii) enhance the electrostatic potential due to basic residues in the cluster, or (iii) induce membrane curvature. Determining the depth of the Phe residues within the membrane is the first step in understanding why they are often associated with basic residues in peripheral membrane proteins.An array of biophysical approaches has shed light on the conformation and location of the MARCKS-(151-175) peptide bound to lipid membranes. EPR spectroscopy (17) and circular dichroism (13) have shown that this peptide adopts an extended conformation when bound to membrane bilayers. Cafiso and co-workers (18, 19) have undertaken an extensive series of EPR studies on MARCKS-(151-175) to probe its location relative to the membrane surface. They systematically substituted amino acids in the MARCKS-(151-175) sequence with cysteines derivatized with nitroxide spin labels and found that spin labels attached at the highly basic and hydrophilic N and C termini of the peptide reside on the aqueous side of the lipid phosphate head group, whereas spin labels attached to the central Phe-containing portions of the peptide are located several angstroms below the lipid head group (17).In this study, we used a complementary technique, magic

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Section: Penetration Of Aromatic Phenylalanine Rings Into Membranesupporting

confidence: 61%

Binding of Peptides with Basic and Aromatic Residues to Bilayer Membranes

Zhang

Crocker

McLaughlin

et al. 2003

Journal of Biological Chemistry

109

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“…Such effects were observed for the fatty acid myristate (ApK= +2.1) and for basic tertiary amine anaesthetics (ApK=-1.0-1.5) in neutral DMPC liposomes [38].…”

Section: Contributions To the Interfacial Apkmentioning

confidence: 79%

On the physical basis for the cis‐positive rule describing protein orientation in biological membranes

Krishtalik

1995

FEBS Letters

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The topology of hydrophobic intramembrane proteins is characterized by a statistical asymmetry in the distribution of positively-charged residues on the two sides of the membrane, the 'inside-or cis-positive rule'. A mechanism is proposed involving only neutral residue transfer. For a tightly bound polypeptide adsorbed on the membrane and not at equilibrium, the pK values of the ionic residues related to dissociation of the proton into the aqueous phase bulk are increased because of interaction with the negative charges at the membrane surface. The pK shift would selectively neutralize aspartate and glutamate residues, favoring their translocation across the membrane, while stabilizing the impermeant positively charged state of lysine and arginine residues.

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“…[2] are included and correspond to both the higher (K b ) and lower (K b1 ) SDS concentration ranges: an example of the fitted curves is presented in Fig. 6a and b for CPZ at pH 7.0.…”

Section: (B) Binding Constants Of the Drugs To Micellesmentioning

confidence: 99%

“…The aromatic rings are responsible for significant absorption and, in many cases, for fluorescence properties, which vary with the protonation state and the local enviroment of the drug, and thus can be used to probe the drug interaction with membrane systems. The selective biodistribution of an ionic drug in tissues and membranes (1) depends on its selfinteracting properties (aggregation) and complex interactions with its molecular surroundings (2). The importance of aggregation vs monomer binding has been widely recognized (3).…”

Section: Introductionmentioning

confidence: 99%