A wide variety of topics are being taught in U.S. medical schools under the umbrella of CAM. For the most part, the instruction appears to be founded on the assumption that unconventional therapies are effective, but little scientific evidence is offered. This approach is questionable, especially since mainstream medicine owes much of its success to a foundation of established scientific principles.
Inside-out vesicles prepared from human red blood cells took up Ca2+ by an active transport process. Membranes from the same red blood cells displayed Ca2+-activated, Mg2+-dependent adenosine triphosphatase activity. Both the initial rate of Ca2+ transport and the (Ca2+ + Mg2+)-adenosine triphosphatase activity were increased approximately twofold by the calcium binding protein, calmodulin. Activities in the absence of added calmodulin were termed basal activities. Calmodulin-activated Ca2+ transport and adenosine triphosphatase activities could be antagonized in a relatively selective fashion by the phenothiazine tranquilizer drug, trifluoperazine. High concentrations of trifluoperazine also inhibited basal Ca2+ transport and adenosine triphosphatase activity. By contrast, calmodulin binding protein from beef brain selectively antagonized the effect of calmodulin on Ca2+ transport with no inhibition of basal activity. Ruthenium red antagonized calmodulin-activated and basal activity with equal potency. The results demonstrate that although phenothiazines can act as relatively selective antagonists of calmodulin-induced effects, other effects are possible and cannot be ignored. Calmodulin-binding protein may be a useful tool in the analysis of calmodulin functions. Ruthenium red probably interacts with Ca2+ pump adenosine triphosphatase at a site not related to calmodulin.
The data summarized and presented in this paper are consistent with the interpretation that CaM participates in the regulation of the plasma membrane calcium pump. Certain drugs, such as phenothiazines can antagonize CaM. Ca2+ loading of RBCs promotes CaM binding to RBC membranes and results in decreased responsiveness of the [Ca2+ + Mg2+)-ATPase to CaM. The latter effect may be mediated by a Ca2+ activated transglutaminase. Activation of (Ca2+ + Mg2+)-ATPase by CaM in vitro was shown not to be instantaneous, probably because of slow binding. CaM binding to isolated RBC membranes exhibits a Ca2+ dependence that is similar to that for activation of the (Ca2+ + Mg2+)-ATPase, and CaM binding does not decrease at high [Ca2+]s. Calculations based on assumed values for RBC [Ca2+], [CaM], and binding affinities of Ca2+ for CaM and CaM(Ca2+)n for the Ca2+ pump ATPase resulted in the tentative conclusion that most pump sites are occupied by CaM in the RBC in vivo. This conclusion, and the relatively slow time course of the CaM effect on (Ca2+ + Mg2+)-ATPase prompt us to suggest that, for all practical purposes, CaM is a subunit of the Ca2+ pump ATPase in vivo.
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