Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Review article The plasma membrane calcium pumps—The old and the new Asma Zaidi ⁎ , Mercy Adewale, Lauren McLean, Paul Ramlow Division of Basic Sciences, Kansas City University of Medicine and Biosciences, 1750 Independence Avenue, Kansas City, MO 64106, USA ARTICLE INFO Keywords: Plasma membrane Ca 2+ -ATPase Calcium overload Brain aging Oxidative stress Neurodegeneration ABSTRACT The plasma membrane Ca 2+ -ATPase (PMCA) pumps play a critical role in the maintenance of calcium (Ca 2+ ) homeostasis, crucial for optimal neuronal function and cell survival. Loss of Ca 2+ homeostasis is a key precursor in neuronal dysfunction associated with brain aging and in the pathogenesis of neurodegenerative disorders. In this article, we review evidence showing age-related changes in the PMCAs in synaptic plasma membranes (SPMs) and lipid raft microdomains isolated from rat brain. Both PMCA activity and protein levels decline progressively with increasing age. However, the loss of activity is disproportionate to the reduction of protein levels suggesting the presence of dysfunctional PMCA molecules in aged brain. PMCA activity is also diminished in post-mortem human brain samples from Alzheimer’s disease and Parkinson’s disease patients and in cell models of these neurodegenerative disorders. Experimental reduction of the PMCAs not only alter Ca 2+ homeostasis but also have diverse effects on neurons such as reduced neuritic network, impaired release of neurotransmitter and increased susceptibility to stressful stimuli, particularly to agents that elevate intracellular Ca 2+ [Ca 2+ ] i . Loss of PMCA is likely to contribute to neuronal dysfunction observed in the aging brain and in the development of age-dependent neurodegenerative disorders. Therapeutic (pharmacological and/or non-phar- macological) approaches that can enhance PMCA activity and stabilize [Ca 2+ ] i homeostasis may be capable of preventing, slowing, and/or reversing neuronal degeneration. 1. Introduction Calcium (Ca 2+ ) is an important second messenger molecule that plays a crucial role in regulating diverse neuronal functions such as release of neurotransmitters, signal transduction, induction of gene expression and synaptic plasticity [1–3]. The intracellular Ca 2+ [Ca 2+ ] i needs to be tightly controlled in terms of time, space and amplitude to enable it to serve as a signaling molecule [4]. Upon stimulation, Ca 2+ enters neurons via the voltage-gated Ca 2+ channels (VGCC) and/or li- gand-gated Ca 2+ channels but within a matter of milliseconds, the 10,000-fold Ca 2+ gradient that exists across the plasma membrane under resting conditions is restored. This enables the neuron to prepare for the next round of stimulation. The return to baseline [Ca 2+ ] i is the consequence of a complex interplay between several Ca 2+ regulating systems including buffering by the Ca 2+ binding proteins calmodulin (CaM) and calbindin, uptake into the mitochondria, sequestration into the endoplasmic reticulum by the sarco-endoplasmic reticulum Ca 2+ - ATPase (SERCA), and transport across the plasma membrane by the sodium Ca 2+ exchanger (NCX) and the plasma membrane Ca 2+ -ATPase (PMCA) [5,6]. The PMCA plays a critical role in fine tuning [Ca 2+ ] i and main- taining neuronal Ca 2+ homeostasis [7]. It extrudes cytoplasmic Ca 2+ to the extracellular milieu via active transport by using energy from ATP hydrolysis. The PMCA is an integral membrane protein with 10 trans- membrane domains. The functional domains are present in the cytosol with the active site localized between the 4th and 5th transmembrane domains. This region forms an intracellular loop which houses the ATP binding site and the phosphorylation site. The PMCA is physiologically stimulated by the Ca 2+ sensor protein CaM [8]. Under resting condi- tions (low cytosolic Ca 2+ ), the protein is in its auto-inhibited state in which the C-terminal auto-inhibitory domain interacts with and blocks the ATP binding site [9]. Increase in [Ca 2+ ] i is accompanied by the binding of Ca 2+ to CaM, conformational changes in CaM, and inter- action of the Ca 2+ -CaM complex with the auto-inhibitory domain which then dissociates from the active site [9,10]. Exposure of the ac- tive site allows for ATP binding, phosphorylation of a conserved as- partate residue, and transport of Ca 2+ to the extracellular environment. There are four PMCA isoforms each with their own set of splice variants [11,12]. Among these isoforms, PMCA1 is considered to be the housekeeping form being ubiquitously expressed in all tissue types. PMCA4 null mice are male sterile, suggesting a more specialized role for this isoform [13]. PMCA2 and PMCA3 are tissue-specific, being ex- pressed exclusively in excitable cells such as neurons and skeletal muscle cells [14]. PMCA isoforms and their variants have different http://dx.doi.org/10.1016/j.neulet.2017.09.066 Received 15 July 2017; Received in revised form 29 September 2017; Accepted 30 September 2017 ⁎ Corresponding author. E-mail address: azaidi@kcumb.edu (A. Zaidi). Neuroscience Letters 663 (2018) 12–17 0304-3940/ © 2017 Elsevier B.V. All rights reserved. T