Plasma membrane Ca2+-ATPases: Targets of oxidative stress in brain aging and neurodegeneration

Abstract

The plasma membrane Ca²⁺-ATPase (PMCA) pumps play an important role in the maintenance of precise levels of intracellular Ca²⁺ [Ca²⁺]_i, essential to the functioning of neurons. In this article, we review evidence showing age-related changes of the PMCAs in synaptic plasma membranes (SPMs). PMCA activity and protein levels in SPMs diminish progressively with increasing age. The PMCAs are very sensitive to oxidative stress and undergo functional and structural changes when exposed to oxidants of physiological relevance. The major signatures of oxidative modification in the PMCAs are rapid inactivation, conformational changes, aggregation, internalization from the plasma membrane and proteolytic degradation. PMCA proteolysis appears to be mediated by both calpains and caspases. The predominance of one proteolytic pathway vs the other, the ensuing pattern of PMCA degradation and its consequence on pump activity depends largely on the type of insult, its intensity and duration. Experimental reduction of PMCA expression not only alters the dynamics of cellular Ca²⁺ handling but also has a myriad of downstream consequences on various aspects of cell function, indicating a broad role of these pumps. Age- and oxidation-related down-regulation of the PMCAs may play an important role in compromised neuronal function in the aging brain and its several-fold increased susceptibility to neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and stroke. Therapeutic approaches that protect the PMCAs and stabilize [Ca²⁺]_i homeostasis may be capable of slowing and/or preventing neuronal degeneration. The PMCAs are therefore emerging as a new class of drug targets for therapeutic interventions in various chronic degenerative disorders.

Keywords: Calcium; Neurons; Plasma membrane Ca²⁺-ATPase; Calmodulin; Oxidative stress; Excitotoxicity; Brain aging; Neurodegeneration