title: Altered calmodulin degradation and signaling in non-neuronal cells from Alzheimer's disease patients.
abstract: Previous work indicated that changes in Ca(2+)/calmodulin (CaM) signaling pathway are involved in the control of proliferation and survival of immortalized lymphocytes from Alzheimer's disease (AD) patients. We examined the regulation of cellular CaM levels in AD lymphoblasts. An elevated CaM content in AD cells was found when compared with control cells from age-matched individuals. We did not find significant differences in the expression of the three genes that encode CaM: CALM1, 2, 3, by real time RT-PCR. However, we observed that the half-life of CaM was higher in lymphoblasts from AD than in control cells, suggesting that degradation of CaM is impaired in AD lymphoblasts. The rate of CaM degradation was found to be dependent on cellular Ca(2+) and ROS levels. CaM degradation occurs mainly via the ubiquitin-proteasome system. Increased levels of CaM were associated with overactivation of PI3K/Akt and CaMKII. Our results suggest that increased levels of CaM synergize with serum to overactivate PI3K/Akt in AD cells by direct binding of CaM to the regulatory α-subunit (p85) of PI3K. The systemic failure of CaM degradation, and thus of Ca(2+)/CaM-dependent signaling pathways, may be important in the etiopathogenesis of AD.
authors: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors: Noemí
authors: N
authors: Esteras
authors: Úrsula
authors: Ú
authors: Muñoz
authors: Carolina
authors: C
authors: Alquézar
authors: Fernando
authors: F
authors: Bartolomé
authors: Félix
authors: F
authors: Bermejo-Pareja
authors: Ángeles
authors: Á
authors: Martín-Requero
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D002147:Calmodulin; D002118:Calcium