Husebye E S, Flatmark T
Department of Biochemistry, University of Bergen, Norway.
Biochem Pharmacol. 1988 Nov 1;37(21):4149-56. doi: 10.1016/0006-2952(88)90109-8.
The effects of hydrophilic and amphiphilic cations on the activity of phosphatidylinositol (PI) kinase (EC 2.7.1.67) of chromaffin granule ghosts were investigated. The cations studied can be divided into two groups, i.e. (i) compounds with a biphasic response (stimulation and inhibition), and (ii) those with a selective stimulatory effect on the enzyme activity. The cationic amphiphile trifluoperazine belongs to the first group, and stimulated the enzyme activity, maximal at 80 microM (2-fold), with a progressive inhibition at higher concentrations. This biphasic response was shared by a number of structurally related cationic amphiphiles, i.e. the tricyclic antidepressants, imipramine and desipramine, the phenothiazine, chlorpromazine, the miconazole derivative, calmidazolium, the beta-adrenergic agonist, propranolol, compound 48/80, as well as by the hydrophilic cations neomycin and poly-L-lysine. On the other hand, a pure stimulatory effect was observed with the amphiphilic polypeptide mastoparan and the polycationic compound spermidine, whereas ACTH1-39 and ACTH1-24 (peptides structurally related to mastoparan) revealed a slight inhibitory effect. We conclude that all the cations tested including Mg2+, stimulate PI kinase activity rather unspecifically by binding of the positively charged groups to a membrane component, probably the PI kinase itself. This site is different from that mediating the specific inhibition by calcium (Husebye ES and Flatmark T, Biochim Biophys Acta 968: 261-265, 1988). The inhibitory effect of cationic amphiphiles is correlated to their lipid solubility, and represents a perturbation of the membrane structure, but not a solubilization of enzyme or phosphoinositide from the membrane. The inhibitory effect of hydrophilic cations is due to complexation of ATP.
