Abstract
The effects of aromatic compounds in sarcoplasmic reticulum Ca2+-ATPase were investigated. The solubility of the drugs in various organic solvents and water was measured. The ratio between the solubility in organic solvents and that in water (distribution coefficient) was used as an index of their hydrophobicity. The order found was triphenylphosphine greater than diphenylamine greater than 3-nitrophenol greater than 4-nitrophenol greater than 1,3-dihydroxybenzene. The effects observed on the Ca2+-ATPase were correlated with hydrophobicity of the drugs, activation and inhibition being obtained at a lower concentration the greater the distribution coefficient of the drug into organic solvent. In leaky vesicles, the effects of each compound on the ATPase activity varied depending on the Ca2+ concentration in the medium: it inhibited in the presence of 5 microM Ca2+ and activated when the Ca2+ concentration was raised to 2 mM. In intact vesicles, 3- and 4-nitrophenol, diphenylamine, and triphenylphosphine enhanced both the rate of ATP hydrolysis and the amount of Ca2+ accumulated by the vesicles. These four drugs inhibited Ca2+ uptake when ITP was used as substrate. 1,3-Dihydroxybenzene enhanced the amount of Ca2+ accumulated by the vesicles regardless of whether ATP or ITP was the substrate. All five compounds inhibited the phosphorylation of the enzyme by Pi, the efflux of Ca2+, and the synthesis of ATP measured during the reversal of the Ca2+ pump. The results indicate that the hydrophobic character of various organic compounds determines their access to sensitive domains of the membrane-bound calcium pump. Additional specific effects are then produced, depending on the structure of each compound.
Highlights
The effects of each compound on Sarcoplasmic reticulum vesicles wereprepared from rabbit skeletal the ATPase activity varieddepending on the Ca2+con- muscle as described by Eletr and Inesi [20]
Wewere not able to measure the partitioning of the aromatic compounds into the membranes of the sarcoplasmic reticulum vesicles.the concentration dependence of enzyme inhibition (K,) by the various compounds was obtained from the values of
The good correlation between the partition coefficients of shown in Fig. 2; it increases CazCuptake when ATPis used, the aromatic compounds tested (Table I) and the concentra- and it inhibitswhen I T P is used as substrate
Summary
The effects of each compound on Sarcoplasmic reticulum vesicles wereprepared from rabbit skeletal the ATPase activity varieddepending on the Ca2+con- muscle as described by Eletr and Inesi [20]. The CaZ+-ATPasewas centration in the medium: it inhibited in the presence purified from the vesicles accordingto MacLennan [21] and Meissner of 5 MMCa2+and activatedwhen the Ca2+concentration et al [22] Both preparations have a high ATPase activity but are was raised to 2 mM. 3-and 4-nitrophenol, diphenylamine, and triphenylphosphine enhanced both the rateof ATP hydrolysis and the amount of Ca” accumulated by the vesicles These four drugs inhibited Ca2+uptake when ITP was used as substrate. All five compounds inhibited the phosphorylation of the enzyme byPi, the efflux of Ca2+,and thesynthesis of ATP measured during the reversoaflthe Ca” pump. Wewere not able to measure the partitioning of the aromatic compounds into the membranes of the sarcoplasmic reticulum vesicles.the concentration dependence of enzyme inhibition (K,) by the various compounds was obtained from the values of. $ Recipient of a fellowship from Coordenaclo de Aperfeicoamento de Pessoal de Nivel Superior, Brazil
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