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Calmodulin, A Limiting Component

Tran et al. investigated whether calmodulin (CaM) could be a limiting reagent in cellular signaling processes, thus resulting in competition for CaM and providing a mechanism controlling calmodulin-dependent processes. Free CaM and free intracellular Ca2+ concentration [Ca2+]i were measured in endothelial cells treated to enhance the affinity of endothelial nitric oxide synthase (eNOS) for CaM by pharmacologically manipulating the phosphorylation status of eNOS. In cells treated to increase the eNOS-CaM interaction, free CaM was much lower than in untreated cells exposed to the calcium ionophore, ionomycin, and [Ca2+]i was much higher. Depletion of available CaM by either increasing binding to eNOS or expressing a high-affinity CaM biosensor decreased the activity of another CaM target, the plasma membrane Ca2+ pump (PMCA). The effects of CaM depletion were not dependent on eNOS activity, only on CaM-eNOS binding, because the NOS inhibitor L-NAME did not block the effects of CaM depletion. These results suggest that phosphorylation can regulate the affinity of CaM for its targets and that this can contribute to the overall available CaM. Consequently, free CaM concentration, as well as [Ca2+]i, are likely to be important factors controlling cellular signaling involving calcium. These results dovetail with results highlighted in a 24 June 2003 summary, suggesting that sequestration of CaM contributes to potentially lethal increases in calcium that contribute to cell death. Q.-K. Tran, D. J. Black, A. Persechini, Intracellular coupling via limiting calmodulin. J. Biol. Chem. 278, 24247-24250 (2003). [Abstract] [Full Text]