Modulation of Endoplasmic Reticulum Calcium Pump Expression during T Lymphocyte Activation

Abstract

Calcium mobilization from intracellular storage organelles is a key component of the second messenger system inducing cell activation. Calcium transport ATPases associated with intracellular calcium storage organelles play a major role in controlling this process by accumulating calcium from the cytosol into intracellular calcium pools. In this study the modulation of the expression of the sarco-endoplasmic reticulum calcium transport ATPase (SERCA) isoenzymes has been studied in lymphocytes undergoing phorbol myristate acetate and ionomycin-induced activation. In several T lymphocyte cell lines a combined treatment by the two drugs resulted in an approximately 90% decrease of the expression of the calcium pump isoform recognized by the PLIM430 isoform-specific antibody, whereas the expression of the SERCA 2b isoform was increased approximately 2-fold. Phorbol ester or ionomycin applied separately was ineffective. In Jurkat T cells the downmodulation of expression of the SERCA isoform recognized by the PLIM430 antibody appeared concomitantly with the induction of interleukin-2 expression and could be inhibited by the immunosuppressant drug cyclosporine-A. These data indicate that T cell activation induces a selective and cyclosporine-A-sensitive modulation of the expression of the SERCA calcium pump isoforms. This reflects a profound reorganization of the calcium homeostasis of T cells undergoing activation and may open new avenues in the understanding of the plasticity of the calcium homeostasis of differentiating cells and in the pharmacological modulation of lymphocyte function.Calcium as a second messenger is a key component of the cellular signaling network controlling lymphocyte function (Refs. 1-3 and references therein). Activation of the T cell receptor complex and associated coreceptors by antigen presenting cells leads to the formation of two second messengers, diacylglycerol and inositol 1,4,5-trisphosphate (IP 3 ).1 The formation of diacylglycerol results in the activation of various cellular protein kinase C isoenzymes, and the binding of IP 3 to its receptor induces the release of calcium into the cytosol from intracellular calcium storage organelles (1-3). Calcium mobilization from the endoplasmic reticulum also provokes a calcium influx across the plasma membrane (4 -8). These events lead to the activation of several inducible transcription factors such as NFB, NFAT, or AP-1 (9). The induction of the transcription of activation-associated genes, e.g. the gene coding for IL-2 (9, 10), or the ␣ chain of the IL-2 receptor (11) leads to a profound reorganization of the structure and function of the cell, resulting in an activated phenotype. Endoplasmic reticulum associated calcium pumps (SERCA enzymes) accumulate calcium ions from the cytosol by ATP-dependent active transport into endoplasmic reticulum-associated calcium storage organelles (8). Because the increase of cytosolic calcium concentration, as well as the depletion of intracellular calcium pools, generate several activatory signals (5-8), ...

Basal Transcription of the Mouse Sarco(endo)plasmic Reticulum Ca2+-ATPase Type 3 Gene in Endothelial Cells Is Controlled by Ets-1 and Sp1

“…Furthermore, Ets-1 is expressed in the lymphoid organs and in hematopoietic cells (47). This pattern of expression is very similar to that of SERCA3 (3)(4)(5)(6)(7)(8)(9)(10). Because functional EBSs had been identified in numerous promoters of genes that are involved in angiogenesis (see above), these observations, taken together, strongly suggested that Ets-1 was a good candidate for regulating the SERCA3 gene in endothelial cells.…”

“…The SERCA2 gene gives rise to the ubiquitous SERCA2b isoform and to SERCA2a, which is produced mainly in cardiac, slow skeletal, and smooth muscle cells. SERCA3 is present in specific cell types such as: endothelial cells of a wide variety of tissues (4,5); epithelial cells of the trachea, salivary glands, and intestine (4,6); platelets and the hematopoietic cell lineage (7,8); pancreatic ␤-cells and the acini of salivary glands (9); and brain Purkinje cells (6). SERCA3 is expressed early in development, and it is present in the heart tube and in the yolk sac at 10 days post-coitum.…”

Biogenesis of endoplasmic reticulum proteins involved in Ca2+ signalling during megakaryocytic differentiation: an in vitro study

“…First, SERCA3 has been shown to be expressed in different cells of haematopoietic origin. Secondly, modulations of SERCA3 expression have been found in platelets of spontaneously hypertensive rats [19,23], and upon lymphocyte activation [61] or granulocytic and monocyte\macrophage differentiation [62]. Accordingly, the analysis of the 5h-untranslated promoter region of the human SERCA3 gene revealed multiple sites for transcription factors including specific haematopoietic factors GATA and Ets.…”

Three Novel Sarco/endoplasmic Reticulum Ca2+-ATPase (SERCA) 3 Isoforms

“…Cell Treatments-Lymphocyte activation and induction of HL-60 cell differentiation were performed as previously described (24,25).…”