Role of plasma membrane calcium ATPase 2 in spinal cord pathology

Abstract

A number of studies have indicated that plasma membrane calcium ATPases (PMCAs) are expressed in the brain and spinal cord and could play important roles not only in the maintenance of cellular calcium homeostasis but also in the survival and function of central nervous system cells under pathological conditions. The different regional and cellular distributions of the various PMCA isoforms and splice variants in the nervous system and the diverse phenotypes of PMCA knockout mice support the notion that each isoform might play a distinct role. Especially in the spinal cord, the survival of neurons and, in particular, motor neurons could be dependent on PMCA2. This is indicated by the knockdown of PMCA2 in pure spinal cord neuronal cultures that leads to cell death via a decrease in collapsing response mediator protein 1 levels. Moreover, the progressive decline in the number of motor neurons in PMCA2-null mice and heterozygous mice further supports this notion. Therefore, the reported reduction in PMCA2 mRNA and protein levels in the inflamed spinal cord of mice affected by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, and after spinal cord contusion injury, suggests that changes in PMCA2 expression could be a cause of neuronal pathology and death during inflammation and injury. Glutamate excitotoxicity mediated via kainate receptors has been implicated in the neuropathology of both EAE and spinal cord injury, and has been identified as a trigger that reduces PMCA2 levels in pure spinal cord neuronal cultures through degradation of the pump by calpain without affecting PMCA2 transcript levels. It remains to be determined which other stimuli modulate PMCA2 mRNA expression in the aforementioned pathological conditions of the spinal cord.

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis

“…Consistent with this, RNAseq analysis (Figure 7(b)) shows increased levels of FcγR2b, FcγR3, and Fcεr1γ in WT EAE mice, while in het-cKO mice, these were increased to a greater extent; and FcγR1, FcγR4, and FcγRt, a neonatal FcγR also expressed in brain (Stamou, Grodzki, van Oostrum, Wollscheid, & Lein, 2018) were increased. We also found (Figure 7c) that mRNA levels for ChAT, VEGF, Glut1, and CRMP1 were decreased in het-cKO samples, genes shown to be needed for motor neuron survival (Fakira & Elkabes, 2010;Stanojlovic et al, 2016). In contrast, caspase-3 levels were not altered, indicating absence of apoptotic cells.…”

“…In the latter models, motor neuron loss reached 46% at 50 days after immunization (Aharoni et al, 2011). We also observed decreases in CRMP1 (collapsing response mediator protein 1) expression, a protein involved in neuritogenesis and growth (Fakira & Elkabes, 2010), and whose levels were reduced in motor neurons following knockdown of plasma membrane calcium ATPase (Kurnellas, Nicot, Shull, & Elkabes, 2005). We also found reduced levels of VEGF-A, a neurotrophic growth factor whose levels are reduced in spinal cords during the course of EAE leading to suppression of VEGFR2 signaling and exacerbated motor neuron loss (Stanojlovic et al, 2016).…”

Plasma Membrane Ca2+-ATPase Isoforms Composition Regulates Cellular pH Homeostasis in Differentiating PC12 Cells in a Manner Dependent on Cytosolic Ca2+ Elevations

“…Therefore, changes in PMCA expression occurring i.e. in ageing brain or spinal cord injury [74] , [75] may profoundly affect cellular metabolic network and disturb mitochondrial function. In view of this, pathological alterations in PMCA expression, in particular PMCA2, may contribute to neurotransmission dysfunctions via a mechanism of mitochondrial depolarization.…”

Anthocyanins suppress the secretion of proinflammatory mediators and oxidative stress, and restore ion pump activities in demyelination

“…Ca 2+ -ATPase also displays ATP-dependent activity, and its role is to regulate intracellular Ca 2+ (iCa 2+ ) concentrations. This enzyme contributes to the signaling pathways triggered by this second messenger and protects cells from excitotoxic damage mediated by elevated iCa 2+ levels [13,14]. Evidence from the literature supports a decrease in both the activity and the expression of these enzymes in the development of axonal loss and MS [15][16][17].…”