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A general mechanism for drug promiscuity: Studies with amiodarone and other antiarrhythmics.

Rusinova R, Koeppe RE, Andersen OS - J. Gen. Physiol. (2015)

Bottom Line: We took advantage of the gramicidin (gA) channels' sensitivity to changes in bilayer properties to determine whether commonly used antiarrhythmics--amiodarone, dronedarone, propranolol, and pindolol, whose pharmacological modes of action range from multi-target to specific--perturb lipid bilayer properties at therapeutic concentrations.Using a gA-based fluorescence assay, we found that amiodarone and dronedarone are potent bilayer modifiers at therapeutic concentrations; propranolol alters bilayer properties only at supratherapeutic concentration, and pindolol has little effect.Using single-channel electrophysiology, we found that amiodarone and dronedarone, but not propranolol or pindolol, increase bilayer elasticity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Biophysics and Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065 Department of Physiology and Biophysics and Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065 rar2021@med.cornell.edu.

No MeSH data available.


Related in: MedlinePlus

A schematic illustration of how amphiphilic drugs can modulate membrane protein function by a bilayer-mediated mechanism and structures of the antiarrhythmics. (A) Schematic representation of the bilayer-mediated regulation of membrane protein function, which arises because the reversible partitioning of the amphiphiles between the aqueous solution and the bilayer–solution interface alters lipid bilayer properties, including the elasticity (Evans et al., 1995; Zhelev, 1998; Bruno et al., 2013) and thus ΔGdef (and therefore ). In the figure, conformations I and II are denoted as “closed” and “open,” respectively. (B) Molecular structures of the antiarrhythmics amiodarone, dronedarone, propranolol, and pindolol.
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fig1: A schematic illustration of how amphiphilic drugs can modulate membrane protein function by a bilayer-mediated mechanism and structures of the antiarrhythmics. (A) Schematic representation of the bilayer-mediated regulation of membrane protein function, which arises because the reversible partitioning of the amphiphiles between the aqueous solution and the bilayer–solution interface alters lipid bilayer properties, including the elasticity (Evans et al., 1995; Zhelev, 1998; Bruno et al., 2013) and thus ΔGdef (and therefore ). In the figure, conformations I and II are denoted as “closed” and “open,” respectively. (B) Molecular structures of the antiarrhythmics amiodarone, dronedarone, propranolol, and pindolol.

Mentions: The lipid bilayer adaptation to a membrane protein’s hydrophobic domain has an associated energetic cost, the bilayer deformation energy (), which varies with changes in protein shape and lipid bilayer properties (Nielsen et al., 1998; Nielsen and Andersen, 2000; Partenskii and Jordan, 2002). Different protein conformations (e.g., Lundbæk et al., 2010a) are thus likely to be associated with different (Fig. 1 A). This concept is important because the free energy cost () for a conformational change (between states I and II) is determined by the contributions from the membrane protein () and the bilayer () (e.g., Lundbæk et al., 2010a):(1)ΔGtotalI→II=ΔGproteinI→II+(ΔGdefII−ΔGdefI)=ΔGproteinI→II+ΔGbilayerI→II,where and vary with changes in bilayer elasticity, thickness, and intrinsic lipid curvature (Andersen et al., 2007), which in turn means that (and therefore ) will vary with changes in bilayer properties (except when the changes in equal the changes in ).


A general mechanism for drug promiscuity: Studies with amiodarone and other antiarrhythmics.

Rusinova R, Koeppe RE, Andersen OS - J. Gen. Physiol. (2015)

A schematic illustration of how amphiphilic drugs can modulate membrane protein function by a bilayer-mediated mechanism and structures of the antiarrhythmics. (A) Schematic representation of the bilayer-mediated regulation of membrane protein function, which arises because the reversible partitioning of the amphiphiles between the aqueous solution and the bilayer–solution interface alters lipid bilayer properties, including the elasticity (Evans et al., 1995; Zhelev, 1998; Bruno et al., 2013) and thus ΔGdef (and therefore ). In the figure, conformations I and II are denoted as “closed” and “open,” respectively. (B) Molecular structures of the antiarrhythmics amiodarone, dronedarone, propranolol, and pindolol.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4664825&req=5

fig1: A schematic illustration of how amphiphilic drugs can modulate membrane protein function by a bilayer-mediated mechanism and structures of the antiarrhythmics. (A) Schematic representation of the bilayer-mediated regulation of membrane protein function, which arises because the reversible partitioning of the amphiphiles between the aqueous solution and the bilayer–solution interface alters lipid bilayer properties, including the elasticity (Evans et al., 1995; Zhelev, 1998; Bruno et al., 2013) and thus ΔGdef (and therefore ). In the figure, conformations I and II are denoted as “closed” and “open,” respectively. (B) Molecular structures of the antiarrhythmics amiodarone, dronedarone, propranolol, and pindolol.
Mentions: The lipid bilayer adaptation to a membrane protein’s hydrophobic domain has an associated energetic cost, the bilayer deformation energy (), which varies with changes in protein shape and lipid bilayer properties (Nielsen et al., 1998; Nielsen and Andersen, 2000; Partenskii and Jordan, 2002). Different protein conformations (e.g., Lundbæk et al., 2010a) are thus likely to be associated with different (Fig. 1 A). This concept is important because the free energy cost () for a conformational change (between states I and II) is determined by the contributions from the membrane protein () and the bilayer () (e.g., Lundbæk et al., 2010a):(1)ΔGtotalI→II=ΔGproteinI→II+(ΔGdefII−ΔGdefI)=ΔGproteinI→II+ΔGbilayerI→II,where and vary with changes in bilayer elasticity, thickness, and intrinsic lipid curvature (Andersen et al., 2007), which in turn means that (and therefore ) will vary with changes in bilayer properties (except when the changes in equal the changes in ).

Bottom Line: We took advantage of the gramicidin (gA) channels' sensitivity to changes in bilayer properties to determine whether commonly used antiarrhythmics--amiodarone, dronedarone, propranolol, and pindolol, whose pharmacological modes of action range from multi-target to specific--perturb lipid bilayer properties at therapeutic concentrations.Using a gA-based fluorescence assay, we found that amiodarone and dronedarone are potent bilayer modifiers at therapeutic concentrations; propranolol alters bilayer properties only at supratherapeutic concentration, and pindolol has little effect.Using single-channel electrophysiology, we found that amiodarone and dronedarone, but not propranolol or pindolol, increase bilayer elasticity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Biophysics and Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065 Department of Physiology and Biophysics and Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065 rar2021@med.cornell.edu.

No MeSH data available.


Related in: MedlinePlus