The role of plasma membrane CA sup 2 sup Pumps PMCAs in pathologies of mammalian cells

Abstract

The biochemical function of the plasma membrane calcium ATPases (PMCAs) is the extrusion of cytosolic Ca2+ from the cell. Although this general function is well documented, the role of the complex isoform diversity and especially the contribution of specific isoforms to pathological conditions is less well understood. No human disease has been linked to a defect in any of the four PMCA genes. Nevertheless, isoforms do not have redundant functions, as shown by the indispensable role of PMCA2 demonstrated in transgenic mice. This review summarizes the results of recent analysis of the PMCA dysregulation in diseased cells or model systems of pathological conditions, including both acute disorders like hypoxia/ischemia and seizure, and slowly progressing dysfunctions like Alzheimer's disease, hypertension, diabetes and aging. Abnormalities in PMCA or its regulators have been described in various organs, reflected in changes of expression levels or in modifications or proteolysis of the PMCA protein. Changes of PMCA function are often detected in cell types different from the specific type involved in the pathology, pointing to more general defects. Examples are erythrocytes in diabetes and blood platelets in hypertension. The changes suggest the significance of PMCA in Ca2+ homeostasis both in excitable and non-excitable cells.

Molecular alterations in the cerebellum of the plasma membrane calcium ATPase 2 (PMCA2)-null mouse indicate abnormalities in Purkinje neurons

“…In fact, an increase in the density of Purkinje neurons and a reduction in the thickness of the molecular layer in the cerebellum of PMCA2-null mice have been documented (Kozel et al, 1998). Additional studies further pinpoint the importance of PMCA2 in the function of other CNS regions (Lehotsky et al, 2002). Loss of motor neurons in the spinal cord of PMCA2-null and dfw 2J mice has recently been reported .…”

Effects of Estrogen on PMCA 2 and 4 in Human Fibroblast-like Synovial Cells and Mouse Macrophage-like Cells

“…since, estrogen affected all detectable PMca isoforms in both studied cells; we decline to conclude any specific PMCA isoform specificity, and rather suggest that the effects of estrogen are generalized, awaiting further investigations. gest a disturbance in cellular function due to elevated intracellular ca 2+ as mentioned [18,19], we tend to consider the process is more complex, based on the reported intrinsic antioxidant activity of estrogen [6]. Meanwhile, 1 hour treatments of 17β-estradiol demonstrated non-significant effects on Ca 2+ -atPase activity, both in the presence or absence of cycloheximide (data not shown), denoting that such effects of 17β-estradiol are rather genomic in nature.…”

“…Meanwhile, the normal physiological process of aging reduces the functional capacities of ca 2+ -ATPase due to oxidative modifications of protein molecules [19][20][21][22][23]. such progressive decline of ca 2+ -atPase activity with age has been reported to be of approximately 35 % in aging rat brain synaptosomal membranes [24].…”

“…For whole cell lysate extraction, at confluence, media were aspirated, cells were washed with dulbecco ' s phosphate buffered saline (PBs) without calcium eFFects oF estRoGeN oN PMca 2 aNd 4 attention was drawn mainly to disruption of ca 2+ homeostasis due to its implication in different pathological conditions as ischemia, stroke, and cell death; in which excess intracellular ca 2+ can lead to free radicals [18,19]. Meanwhile, the normal physiological process of aging reduces the functional capacities of ca 2+ -ATPase due to oxidative modifications of protein molecules [19][20][21][22][23].…”

Lack of evidence for regulation of cardiac P-type ATPases and MAP kinases in transgenic mice with cardiac-specific overexpression of constitutively active α1B-adrenoceptors

“…It is well known that some members, such as Na + /K + -ATPase α 2 isoform and sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA2), are down-regulated by cardiac stress associated with adrenergic stimulation and may progress to hypertrophy and failure (19,20). For cardiac plasmalemmal Ca 2+ -ATPase (PMCA), an early expression increase and further decline apparently reflect an initial adaptation to facilitate calcium removal and are the basis of more persistent cardiac dysfunction, respectively (21).…”