Molecular mechanisms of zinc action on cells.

We have postulated that the sickle erythrocyte becomes membrane damaged at least partly due to excessive accumulation of calcium and then to excessive calmodulin activation (42). We have found that zinc therapy in sickle cell anemia improves the membrane status of the sickle cells (53). We have some evidence that zinc is an inhibitor of calmodulin functions, and postulate that zinc's beneficial membrane effect in sickle cell anemia is due to its calmodulin inhibitory properties (42). This reasoning opens the therapeutic door to other calmodulin inhibitors, such as the phenothiazines, which coincidentally, had already been shown to have antisickling properties years ago (59). The phenothiazines "expand" the red cell membrane, a property shown by Seeman (60) to be shared with a wide variety of drugs. If membrane expansion is due to calmodulin inhibition as we believe (42), then all of the membrane expanding drugs share the potential for antisickling properties. These ideas, if correct, rationalize under one mechanism, the reported antisickling properties of a diverse group of drugs, including zinc, procaine, the phenothiazines and most recently, ceteidil. If these possible new insights into the mechanism of antisickling membrane therapy, namely CAC inhibition in sickle cells, lead to a rational and successful approach to therapy in sickle cell anemia, it will be because of the precedent provided by understanding the action of zinc.