The relationship between the effects of drugs on bilayer stability and on protein kinase C activity

doi:10.1016/0009-2797(87)90044-5

Chemico-Biological Interactions

Volume 63, Issue 3, 1987, Pages 239-247

https://doi.org/10.1016/0009-2797(87)90044-5 Get rights and content

Abstract

A variety of substances of diverse structure have been shown to affect the activity of protein kinase C. Many of the agents which affect protein kinase C activity also markedly shift the bilayer to hexagonal phase transition temperature of phosphatidylethanolamines. Although one of the more potent activators of protein kinase C, diacylglycerols, are effective destabilizers of the bilayer phase of membranes, this is not a general property of all protein kinase C activators nor are inhibitors of this enzyme bilayer stabilizing agents. However, if we consider only compounds which are uncharged or are zwitterionic, then those which promote the conversion of phospholipid bilayers to the hexagonal phase are all activators of protein kinase C, while those which stabilize the bilayer phase are protein kinase C inhibitors. Among charged substances, all of those which are negatively charged are activators of protein kinase C, while all of the positively charged compounds are protein kinase C inhibitors.

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Note that it is the tendency rather than the presence of these nonbilayer structures that, it has been claimed, facilitates the activity of these enzymes. This tendency has actually been measured by following the decrease in the Lα to HII transition (TH) in phospholipids such as palmitoyloleylphosphatidylethanolamine and dielaidoylglycerophosphoethanolamine [36–39], and the results obtained have been extrapolated to other membranes. This method has been used to predict the activating or inhibiting effect of a number of compounds on PKC; those decreasing TH will be expected to be activators (such as 5b-cholan-24-ol or eicosane) and those increasing TH will be expected to behave as inhibitors (such as Z-Gly-Leu-NH2, or cyclosporine A).
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We (and others) have consistently detected increases in PK-C activity induced by a variety of lipophilic compounds (14,15,25,50–52), which by themselves do not activate PK-C, but destabilize bilayers by increasing their propensity to adopt nonbilayer lipid phases. Conversely, compounds that decrease this propensity (i.e., seem to stabilize bilayers) attenuate PK-C activity (50–52). The simplest explanation of these observations is that the bilayer instability observed as the increased propensity to adapt nonbilayer lipid phases is an important factor in PK-C activation.
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The relationship between the effects of drugs on bilayer stability and on protein kinase C activity

Abstract

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.