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Ion Channels and Transporters in Lymphocyte Function and Immunity

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Ion Channels and Transporters in Lymphocyte Function and Immunity REVIEWS Ion channels and transporters in lymphocyte function and immunity Stefan Feske1, Edward Y. Skolnik2 and Murali Prakriya3 Abstract | Lymphocyte function is regulated by a network of ion channels and transporters in the plasma membrane of B and T cells. These proteins modulate the cytoplasmic concentrations of diverse cations, such as calcium, magnesium and zinc ions, which function as second messengers to regulate crucial lymphocyte effector functions, including cytokine production, differentiation and cytotoxicity. The repertoire of ion-conducting proteins includes calcium release-activated calcium (CRAC) channels, P2X receptors, transient receptor potential (TRP) channels, potassium channels, chloride channels and magnesium and zinc transporters. This Review discusses the roles of ion conduction pathways in lymphocyte function and immunity. Ion channels and ion transporters function as gateways Store-operated calcium channels Ion channels 2+ Pore-forming transmembrane for charged ions that cannot freely diffuse across lipid Ca is a well-established second messenger in lympho­ proteins that enable the flow of membrane barriers. They regulate the intracellular cytes that regulates proliferation, gene expression, motil- ions down an electrochemical concentration of various ions, such as calcium (Ca2+), ity and other functions. Similarly to in other mamm­alian gradient. magnesium (Mg2+) and zinc (Zn2+). The movement of cell types, the intracellular Ca2+ concentration in unstim- Ion transporters these cations across the plasma membrane depends on ulated B and T cells is maintained at ~50–100 nM, which 4 2+ Pore-forming transmembrane electrical gradients that are maintained in turn by potas- is ~10 -fold lower than the Ca concentration in the proteins that carry ions sium (K+), sodium (Na+) and chloride (Cl−) channels. serum. Following antigen binding to the T cell receptor against a concentration In the past couple of years, fundamental progress has (TCR) or B cell receptor (BCR), the intracellular Ca2+ gradient using energy, been made towards identifying the molecules that con- concentration can increase to ~1 μM1. Several ion chan- typically in the form of ATP. trol the function of Ca2+ release-activated Ca2+ channels nels have been identified in lymphocytes that mediate 2+ 1 (FIG. 1; TABLE 1) 1Department of Pathology, (CRAC channels) — which are the predominant antigen Ca influx . In the following sections, we 2+ New York University Langone receptor-activated Ca channels in lymphocytes — and discuss store-operated CRAC channels as well as P2X Medical Center, New York, channels that mediate Mg2+ and Zn2+ influx in T cells. purinoreceptor channels, transient receptor potential New York 10016, USA. We discuss the mechanisms that regulate the function of (TRP) channels and voltage-gated Ca2+ (Ca ) channels. 2Helen L. and Martin V S. Kimmel Center for Biology these ion channels in lymphocytes and review their roles and Medicine at the Skirball in immunity and their emerging potential for therapeutic CRAC channels. Antigen binding by the TCR or BCR Institute for Biomolecular immunomodulation. is coupled — via protein tyrosine kinases — to the Medicine; Division of Several other ion channels, pumps and organelles activation of phospholipase Cγ1 (PLCγ1) in T cells Nephrology, Department of are also required for the regulation of ion homeostasis and PLCγ2 in B cells and the generation of the lipid Medicine; and Department of 2+ Pharmacology, New York in lymphocytes. For example, transient increases in the metabolite InsP3. InsP3 promotes the release of Ca 2+ 2+ University Langone Medical intracellular Ca concentration are mediated by the from ER stores, and this leads to Ca influx across the Center, New York, release of Ca2+ from endoplasmic reticulum (ER) stores plasma membrane, a process termed store-operated Ca2+ New York 10016, USA. via Ca2+-permeable inositol‑1,4,5‑trisphosphate receptor entry (SOCE)2 (FIGS 1,2). The store-operated Ca2+ chan- 3Department of Molecular ryanodine receptor Pharmacology and Biological (InsP3 receptor) and (RYR) channels. nels of T cells, known as CRAC channels, have been 2+ 3,4 Chemistry, Northwestern Conversely, Ca is cleared from the cytoplasm by uptake extensively characterized and are distinguished by an University, Feinberg School of into mitochondria via the mitochondrial Ca2+ uniporter extremely high ion selectivity for Ca2+ and a low conduct- Medicine, Chicago, (MCU)190,191 and into the ER via sarcoplasmic/endoplas- ance5 (TABLE 1). CRAC channels are activated through Illinois 60611, USA. mic reticulum Ca2+ ATPases (SERCAs) and by Ca2+ export the binding of the ER Ca2+ sensors stromal interaction Correspondence to S.F. plasma membrane Ca2+ ATPases e-mail: [email protected] through (PMCAs). Owing molecule 1 (STIM1) and STIM2 to the CRAC channel doi:10.1038/nri3233 to space limitations, these intracellular ion channels proteins ORAI1, ORAI2 and ORAI3 (also known as Published online 15 June 2012 and transporters are not discussed here. CRACM1, CRACM2 and CRACM3)6. 532 | JULY 2012 | VOLUME 12 www.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS TCR BCR Ca2+ >> Mg2+, Na+ Ca2+, Na+, Mg2+ ORAI1 CRAC Ca2+ release-activated Ca2+ ORAI2? channel P2X 2+ –3 channels ORAI3? [Ca ]o ~10 M (CRAC channels). Highly 2+ –7 2+ [Ca ]i ~10 M (resting) Ca -selective ion channels ζ ζ 2+ –6 [Ca ]i ~10 M (activated) Negative located in the plasma Igα Igβ – membrane membrane that are encoded – potential by ORAI proteins. – (–60 mV) PLCγ1 PLCγ2 SOCE Inositol‑1,4,5‑trisphosphate K 3.1 receptor Ca2+ – Ca (InsP receptor). A – 3 InsP3 2+ Ca -permeable channel STIM1 or K+ located in the membrane of STIM2 K 1.3 the endoplasmic reticulum (ER) – V InsP R that mediates the release of 3 – 2+ Ca from ER stores following SERCA Ca2+ Calcineurin Na+ binding by the second Ca2+ ER TRPM4 messenger InsP . 3 2+ –3 [Ca ]ER ~0.5–1x10 M Ryanodine receptor P NFAT (RYR). A Ca2+-permeable channel located in the membrane of the sarcoplasmic NF-κB Cytokine expression reticulum (SR) and p50 p65 endoplasmic reticulum (ER) CREB MEF2 NFAT Differentiation Proliferation that mediates the release of Cytoplasm Nucleus Ca2+ from the SR or ER stores following binding by the second messenger cyclic ADP-ribose or Ca2+ itself. Figure 1 | Ion channels regulating calcium signalling in lymphocytes. Ca2+ release-activated Ca2+ (CRAC) channels are activated following the engagement of antigen receptors (that is, T cell receptors (TCRs)Nature or B cell Reviews receptors | Immunology (BCRs)). Sarcoplasmic/endoplasmic This is mediated through the activation of phospholipase Cγ (PLCγ), the production of inositol‑1,4,5‑trisphosphate reticulum Ca2+ ATPases (InsP ) and the release of Ca2+ from endoplasmic reticulum (ER) Ca2+ stores1,6,17. The ensuing activation of stromal 2+ 3 (SERCAs). Ca pumps located interaction molecule 1 (STIM1) and STIM2 results in the opening of ORAI1 CRAC channels and store-operated Ca2+ entry in the membrane of the (SOCE) (for details, see FIGS 2,3). Sustained Ca2+ influx through CRAC channels leads to the activation of Ca2+-dependent endoplasmic reticulum (ER) that move Ca2+ from the enzymes and transcription factors, including calcineurin and nuclear factor of activated T cells (NFAT). P2X receptors, 2+ 2+ cytoplasm into the ER through such as P2X4 and P2X7, are non-selective Ca channels activated by extracellular ATP. Ca influx in lymphocytes the hydrolysis of ATP. depends on the gradient between the extracellular Ca2+ concentration (~1 mM) and the intracellular Ca2+ concentration + + (~0.1 μM) and on an electrical gradient established by two K channels (namely, KV1.3 and KCa3.1) and the Na -permeable Plasma membrane Ca2+ channel TRPM4 (transient receptor potential cation channel M4)76,92. CREB, cAMP-responsive-element-binding protein; ATPases InsP3R, InsP3 receptor; MEF2, myocyte-specific enhancer factor 2; NF-κB, nuclear factor-κB; SERCA, sarcoplasmic/ (PMCAs). A family of ion endoplasmic reticulum Ca2+ ATPase. transport ATPases located in the plasma membrane that export Ca2+ from the cytoplasm. Identification of ORAI1. An important milestone in the channel protein and appears to be the predominant iso- 6,17 Store-operated Ca2+ entry identification of ORAI1 as the prototypical CRAC chan- form mediating SOCE in lymphocytes . By contrast, (SOCE). A Ca2+-influx process nel was the discovery that human patients with a severe there is no direct functional or genetic evidence for a role triggered by the depletion of form of combined immunodeficiency (CID) lack func- of ORAI2 or ORAI3 channels in immune cells as yet. 2+ endoplasmic reticulum Ca 7–11 stores and activation of plasma tional CRAC channels and SOCE in T cells . ORAI1 membrane ORAI Ca2+ channels was identified nearly simultaneously by three laborato- Activation of CRAC channels. The activation of ORAI by STIM proteins. ries as the gene encoding this CRAC channel by linkage CRAC channels involves a complex series of coordinated analysis in patients with CID and using RNA interfer- steps, during which STIM proteins fulfil two crucial roles. Ion selectivity ence (RNAi) screens for regulators of SOCE and nuclear First, they sense the depletion of ER Ca2+ stores, and sec- The specificity of an ion factor of activated T cells 12–14 channel for a particular species (NFAT) function . ORAI1 is ond, they communicate store depletion to the CRAC 18–20 2+ of ion, for example Ca2+, Mg2+, a widely expressed surface glycoprotein with four pre- channels
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