Decoding calcium signaling

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Date: Jan. 7, 2005
From: Science(Vol. 307, Issue 5706)
Publisher: American Association for the Advancement of Science
Document Type: Article
Length: 1,557 words
Lexile Measure: 1540L

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Calcium ions ([Ca.sup.2+]) may be the most widely used second messenger molecules in biology. Indeed, [Ca.sup.2+] is essential for early development of organisms, immune responses, and even for remembering what you are about to read. The diverse tasks of [Ca.sup.2+] raise the question of the molecular origins of specific [Ca.sup.2+] responses. Two recent papers in Science, by Badou et al. on page 117 of this issue (1) and by Launay et al. (2), identify new players that regulate the movement of [Ca.sup.2+] into and out of cells, providing a more complete understanding of [Ca.sup.2+] responses in the immune system.

Activation of the T cell receptor (TCR) by ligand initiates a rapid influx of [Ca.sup.2+] into T cells. This leads to the activation of a phosphatase called calcineurin and the subsequent nuclear import and assembly of NFAT transcription complexes, which switch on and off the expression of genes essential for T cell development and function (3). Calcineurin is the target of the immunosuppressive drags cyclosporine A and FK506, the discovery of which ushered in the modern era of organ transplantation. The importance of [Ca.sup.2+]/calcineurin in immune responses and transplantation therapy has generated great interest in how [Ca.sup.2+] signals are regulated. Badou and colleagues examined the lethargic mouse (1), which carries a mutation in the [[beta].sub.4] subunit of the L-type voltage-gated [Ca.sup.2+] channel ([Ca.sub.V]1). Previous work showed that L-type [Ca.sup.2+] channels are essential for calcineurin activation and NFAT function in neurons (4). Hence it was possible that these channels might also be important for NFAT-dependent transcription in lymphocytes. Indeed, CD[4.sup.+] T cells from [[beta].sub.4]-mutant mice exhibit defects in [Ca.sup.2+] entry in response to TCR signaling, are defective in NFATc1 and NFATc2 dephosphorylation, and exhibit severe defects in cytokine production. But what role do these voltage-gated channels play in the activation of nonexcitable cells such as T lymphocytes?

T cells express many different ion channels in their plasma and endoplasmic reticulure (ER) membranes. These channels coordinately regulate the initial [Ca.sup.2+] spike and sustained [Ca.sup.2+] elevation after antigenic stimulation of T cells. In a resting T cell, [K.sub.V] channels regulate the flow of potassium ions ([K.sup.+]) out of the cell, and sarco-endoplasmic reticulum [Ca.sup.2+]-ATPases (SERCA) transport [Ca.sup.2+] into the intracellular stores. The resulting resting potential is about -65 mV. When T cells are stimulated by binding of antigenic peptide associated with major histocompatibility...

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Gale Document Number: GALE|A127194610