Calmodulin, zinc, and calcium in cellular and membrane regulation: An interpretive review

A considerable amount of work in recent years has indicated that the intracellular effects of calcium are mediated primarily by calcium‐binding proteins. One of the most important of these proteins is a 17,000‐molecular weight protein–calmodulin. Calmodulin, when activated by calcium, has the potential to activate many enzymes and to stimulate many intracellular events. While calcium is required for many types of cellular activations, zinc tends to be a cellular inhibitor. It appears that zinc is antagonistic to calcium, tending to inhibit the same cellular reactions triggered by an influx of intra‐cellular calcium. Recent investigations have led us to hypothesize that the zinc‐calcium antagonism mentioned above may be the result of inhibitory effects of zinc on calmodulin‐stimulated functions. This inhibition may operate through binding of zinc to the target proteins of calmodulin or through binding of zinc to calmodulin after the calmodulin is complexed to protein. This area will be reviewed in the first part of this paper. In the erythrocyte, excessive intracellular calcium causes hemoglobin retention by erythrocyte membranes and causes erythrocyte shrinkage. Both of these events may occur in sickle erythrocytes because of sickling‐induced calcium accumulation. Recent studies suggest that excessive calcium‐activated calmodulin may be responsible for both hemoglobin retention by the membrane and for erythrocyte shrinkage. On the other hand, trifluoperazine — a phenothiazine drug that inhibits the action of calmodulin — causes erythrocyte swelling (membrane expansion). These observations have led us to hypothesize that calmodulin is intimately involved with regulation of the erythrocyte membrane expansion/shrinkage state. The possible role of excessive calcium‐activated calmodulin in inducing abnormalities in the sickle membrane may lead to a more rational therapy aimed at the membrane lesion in this disease. This therapy might involve a combination of inhibitory agents such as zinc and a phenothiazine. In the last part of the review, we present a model for the regulation of membrane shrinkage by calmodulin in equilibrium with membrane expansion by spectrin‐actin phosphorylation. Whether or not this model is right in its basic elements, we hope it will provoke some additional thinking and experimental work. In fact, this entire review should be viewed as interpretive. That is, observations from diverse sources have been put together in an attempt to make sense out of them and, in particular, to provoke thinking and stimulate experimental work in these areas.