Abstract

This study represents an inquiry into the molecular mechanisms whereby the interaction of divalent cations and certain cationic drugs with the erythrocyte membrane produces a marked increase in the modification of membrane amino groups by trinitrobenzenesulfonate (TNBS). A mechanism based on simple neutralization of membrane anionic sites by activator cations was untenable because the incorporation of picryl chloride, an uncharged analogue of TNBS, was also markedly increased in the presence of magnesium or chlorpromazine. Rather, it is suggested that the interaction of activators with membrane components induces configurational changes which alter the accessibility and/or reactivity of membrane protein and phospholipid amino groups. These configurational changes, which were found to require the integrity of both polar and nonpolar regions of phospholipids, may involve alterations in membrane hydration following charge neutralization. The specific membrane perturbations induced by individual activators have been analyzed in terms of effects on the activation energy for TNBS incorporation and also in terms of TNBS labeling patterns of membrane protein and lipid components characteristic of the particular cationic activator.