Calmodulin antagonizes amyloid-β peptides-mediated inhibition of brain plasma membrane Ca2+-ATPase

The synaptosomal plasma membrane Ca2+-ATPase (PMCA) plays an essential role in regulating intracellular Ca2+ concentration in brain. We have recently found that PMCA is the only Ca2+ pump in brain which is inhibited by amyloid-beta peptide (A beta), a neurotoxic peptide implicated in the pathology of Alzheimer's disease (AD) [1], but the mechanism of inhibition is lacking. In the present study we have characterized the inhibition of PMCA by A beta. Results from kinetic assays indicate that A beta aggregates are more potent inhibitors of PMCA activity than monomers. The inhibitory effect of A beta, could be blocked by pretreating the purified protein with Ca2+-calmodulin, the main endogenous activator of PMCA, and the activity of truncated PMCA lacking the calmodulin binding domain was not affected by A beta. Dot-overlay experiments indicated a physical association of A beta with PMCA and also with calmodulin. Thus, calmodulin could protect PMCA from inhibition by A beta by burying exposed sites on PMCA, making them inaccessible to A beta, and also by direct binding to the peptide. These results suggest a protective role of calmodulin against neuronal Ca2+ dysregulation by PMCA inhibition induced by A beta. (C) 2012 Elsevier B.V. All rights reserved.