Sensitivity of the Human Myometrial Adenylate Cyclase to Calcium and Calmodulin

The work examines the effect of inhibitors of cytosolic Ca(2+)-dependent and Ca(2+)-independent phospholipases A2 on bilayer lipid membranes. It was established that trifluoroperazine (TFP) and, to a lesser extent, arachidonyl trifluoromethyl ketone (AACOCF3) and palmitoyl trifluoromethyl ketone (PACOCF3) were able to permeabilize artificial lipid membranes (BLM and liposomes). It was shown that AACOCF3 lowered the temperature of phase transition of DMPC liposomes, inducing disordering of the hydrophobic region of lipid bilayer. TFP disordered membranes both in the hydrophobic region and in the region of hydrophilic heads, this being accompanied by changes in the membrane permeability: appearance of a channel-like BLM activity and leakage of sulforhodamine B from liposomes. In contrast to AACOCF3 and TFP, PACOCF3 increased membrane orderliness in the hydrophobic region (heightened the temperature of phase transition of DMPC liposomes) and in the region of lipid heads. The effectiveness of AACOCF3 and PACOCF3 as inductors of BLM and liposome permeabilization was considerably lower comparatively to TFP. As revealed by dynamic light scattering, incorporation of TFP, AACOCF3 and PACOCF3 into the membrane of liposomes resulted in the increase of the average size of particles in the suspension, presumably due to their aggregation or fusion. The paper discusses possible mechanisms of the influence of phospholipase A2 inhibitors on bilayer lipid membranes.

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Effects of Phospholipase A2 Inhibitors on Bilayer Lipid Membranes

Dubinin

Astashev

Penkov

et al. 2016

J Membrane Biol

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Decreasing estrogen in nonpregnant women lowers uterine myometrial type I nitric oxide synthase protein expression

Weeks¹,

Massmann²,

Monaghan³

et al. 1999

American Journal of Obstetrics and Gynecology

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Trifluoperazine induces domain formation in zwitterionic phosphatidylcholine but not in charged phosphatidylglycerol bilayers

Hendrich

Wesołowska

Michalak

2001

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The interaction of trifluoperazine with the zwitterionic lipids dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine and with anionic dimyristoylphosphatidylglycerol was studied by means of microcalorimetry and fluorescence spectroscopy. Intercalation of drug molecules into the lipid bilayers was confirmed by the observed differential scanning calorimetry peak broadening and the decrease in chain-melting temperatures. For trifluoperazine:lipid mole ratios higher than 0.4 and 0.6 (for dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine, respectively) the deconvolution of transition profiles into two Gaussian components was possible, which suggests phase separation in the studied mixtures. Deconvolution of the thermograms was not possible for any of the drug:dimyristoylphosphatidylglycerol mole ratios studied. To confirm the existence of phase separation in trifluoperazine-phosphatidylcholine mixtures fluorescence spectroscopy experiments were performed using Laurdan as a probe. From the generalised polarisation versus excitation wavelength dependences, recorded at different temperatures, we conclude that a phase separation occurs in the gel state of the studied trifluoperazine-phosphatidylcholine mixtures. We attribute the existence of domains in the bilayer to the dissimilar interactions of two protonation forms of trifluoperazine with phosphatidylcholine molecules. Structural defects present at domain boundaries could be related to the trifluoperazine induced increase of membrane permeability and fluidity. This may partially explain the mechanism of multidrug resistance modulation by trifluoperazine.

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Sensitivity of the Human Myometrial Adenylate Cyclase to Calcium and Calmodulin

Cited by 6 publications

References 6 publications

Effects of Phospholipase A2 Inhibitors on Bilayer Lipid Membranes

Effects of Phospholipase A2 Inhibitors on Bilayer Lipid Membranes

Decreasing estrogen in nonpregnant women lowers uterine myometrial type I nitric oxide synthase protein expression

Trifluoperazine induces domain formation in zwitterionic phosphatidylcholine but not in charged phosphatidylglycerol bilayers

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