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Tweeters, Woofers and Horns: The Complex Orchestration of Calcium Currents in T Lymphocytes.

Nohara LL, Stanwood SR, Omilusik KD, Jefferies WA - Front Immunol (2015)

Bottom Line: T cell receptor (TCR) engagement results in depletion of endoplasmic reticulum (ER) Ca(2+) stores and subsequent sustained influx of extracellular Ca(2+) through Ca(2+) release-activated Ca(2+) (CRAC) channels in the plasma membrane.However, several other important Ca(2+) channels that are instrumental in T cell function also exist.In this review, we discuss the role of additional Ca(2+) channel families expressed on the plasma membrane of T cells that likely contribute to Ca(2+) influx following TCR engagement, which include the TRP channels, the NMDA receptors, the P2X receptors, and the IP3 receptors, with a focus on the voltage-dependent Ca(2+) (CaV) channels.

View Article: PubMed Central - PubMed

Affiliation: Michael Smith Laboratories, University of British Columbia , Vancouver, BC , Canada ; Department of Microbiology and Immunology, University of British Columbia , Vancouver, BC , Canada.

ABSTRACT
Elevation of intracellular calcium ion (Ca(2+)) levels is a vital event that regulates T lymphocyte homeostasis, activation, proliferation, differentiation, and apoptosis. The mechanisms that regulate intracellular Ca(2+) signaling in lymphocytes involve tightly controlled concinnity of multiple ion channels, membrane receptors, and signaling molecules. T cell receptor (TCR) engagement results in depletion of endoplasmic reticulum (ER) Ca(2+) stores and subsequent sustained influx of extracellular Ca(2+) through Ca(2+) release-activated Ca(2+) (CRAC) channels in the plasma membrane. This process termed store-operated Ca(2+) entry (SOCE) involves the ER Ca(2+) sensing molecule, STIM1, and a pore-forming plasma membrane protein, ORAI1. However, several other important Ca(2+) channels that are instrumental in T cell function also exist. In this review, we discuss the role of additional Ca(2+) channel families expressed on the plasma membrane of T cells that likely contribute to Ca(2+) influx following TCR engagement, which include the TRP channels, the NMDA receptors, the P2X receptors, and the IP3 receptors, with a focus on the voltage-dependent Ca(2+) (CaV) channels.

No MeSH data available.


The calcium channels in T cells. T cell receptor (TCR) engagement by a peptide-MHC on an antigen presenting cell (APC) induces protein tyrosine kinases (PTKs) to activate phospholipase Cγ1 (PLCγ1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) from plasma membrane phospholipids to generate diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). Elevated levels of IP3 in the cytosol lead to the release of Ca2+ from IP3Rs located in the endoplasmic reticulum (ER). Ca2+ depletion from the ER induces Ca2+ influx from the extracellular space through the plasma membrane channel, ORAI1. Several additional channels also operate during TCR-mediated Ca2+ signaling. These include plasma membrane IP3R activated by the ligand IP3, transient receptor potential (TRP) channels that can be operated by DAG and SOCE, adenosine triphosphate (ATP)-responsive purinergic P2 (P2X) receptors, glutamate-mediated N-methyl-d-aspartate activated (NMDA) receptors, and voltage-dependent Ca2+ channels (CaV) that may be regulated through TCR signaling events. The mitochondria (MT) also control cytoplasmic Ca2+ levels. Increase in intracellular Ca2+ results in activation of calmodulin–calcineurin pathway that induces NFAT nuclear translocation and transcription of target genes to direct T cell homeostasis, activation, proliferation, differentiation, apoptosis and survival. Within this complex network of Ca2+ signaling, a model of the reciprocal regulation of CaV1 and ORAI1 in T cells has been proposed. (A) Low-level TCR signaling through interactions with self-antigens (i.e., self-peptides/self-MHC molecules) may result in CaV1 (particularly CaV1.4) activation and Ca2+ influx from outside the cell. This allows for filling of intracellular Ca2+ stores and initiation of a signaling cascade to activate a pro-survival program within the naïve T cell. STIM1 is not activated in this scenario and, consequently, ORAI1 remains closed. (B) Strong TCR signaling through engagement by a foreign peptide-MHC induces the downstream signaling events that result in ER Ca2+ store depletion and STIM1 accumulation in puncta in regions of the ER near the plasma membrane allowing interactions with Ca2+ channels. ORAI1 enhances STIM1 recruitment to the vicinity of CaV1 channels. Here, STIM1 can activate ORAI1 while inhibiting CaV1.
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Figure 1: The calcium channels in T cells. T cell receptor (TCR) engagement by a peptide-MHC on an antigen presenting cell (APC) induces protein tyrosine kinases (PTKs) to activate phospholipase Cγ1 (PLCγ1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) from plasma membrane phospholipids to generate diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). Elevated levels of IP3 in the cytosol lead to the release of Ca2+ from IP3Rs located in the endoplasmic reticulum (ER). Ca2+ depletion from the ER induces Ca2+ influx from the extracellular space through the plasma membrane channel, ORAI1. Several additional channels also operate during TCR-mediated Ca2+ signaling. These include plasma membrane IP3R activated by the ligand IP3, transient receptor potential (TRP) channels that can be operated by DAG and SOCE, adenosine triphosphate (ATP)-responsive purinergic P2 (P2X) receptors, glutamate-mediated N-methyl-d-aspartate activated (NMDA) receptors, and voltage-dependent Ca2+ channels (CaV) that may be regulated through TCR signaling events. The mitochondria (MT) also control cytoplasmic Ca2+ levels. Increase in intracellular Ca2+ results in activation of calmodulin–calcineurin pathway that induces NFAT nuclear translocation and transcription of target genes to direct T cell homeostasis, activation, proliferation, differentiation, apoptosis and survival. Within this complex network of Ca2+ signaling, a model of the reciprocal regulation of CaV1 and ORAI1 in T cells has been proposed. (A) Low-level TCR signaling through interactions with self-antigens (i.e., self-peptides/self-MHC molecules) may result in CaV1 (particularly CaV1.4) activation and Ca2+ influx from outside the cell. This allows for filling of intracellular Ca2+ stores and initiation of a signaling cascade to activate a pro-survival program within the naïve T cell. STIM1 is not activated in this scenario and, consequently, ORAI1 remains closed. (B) Strong TCR signaling through engagement by a foreign peptide-MHC induces the downstream signaling events that result in ER Ca2+ store depletion and STIM1 accumulation in puncta in regions of the ER near the plasma membrane allowing interactions with Ca2+ channels. ORAI1 enhances STIM1 recruitment to the vicinity of CaV1 channels. Here, STIM1 can activate ORAI1 while inhibiting CaV1.

Mentions: There is increasing evidence in support of relationships between different types of Ca2+ channels, and one such relationship is the one between CaV1.2 and ORAI1 (122, 123). Following Ca2+ store depletion in the ER, STIM1 oligomers form at ER-plasma membrane junctions, thereby allowing the STIM1 CRAC-activating domain (CAD) to interact with the C-terminus of ORAI1 and CaV1.2 channels. STIM1 activates ORAI1 channels, which then open resulting in sustained Ca2+ entry from the extracellular space. On the other hand, STIM1 blocks Ca2+ influx through CaV1.2 and promotes its internalization (122, 123). It may be possible that strong TCR signaling via engagement by a foreign peptide-MHC may lead to this activation of ORAI1 and inhibition of CaV1 channels (Figure 1). In contrast, weaker TCR signaling through engagement with self-antigens might not elicit STIM1 to localize to the plasma membrane, hence activating CaV and blocking ORAI1. Further investigation regarding the interplay between different Ca2+ channel families will greatly advance the field of Ca2+ channel research.


Tweeters, Woofers and Horns: The Complex Orchestration of Calcium Currents in T Lymphocytes.

Nohara LL, Stanwood SR, Omilusik KD, Jefferies WA - Front Immunol (2015)

The calcium channels in T cells. T cell receptor (TCR) engagement by a peptide-MHC on an antigen presenting cell (APC) induces protein tyrosine kinases (PTKs) to activate phospholipase Cγ1 (PLCγ1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) from plasma membrane phospholipids to generate diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). Elevated levels of IP3 in the cytosol lead to the release of Ca2+ from IP3Rs located in the endoplasmic reticulum (ER). Ca2+ depletion from the ER induces Ca2+ influx from the extracellular space through the plasma membrane channel, ORAI1. Several additional channels also operate during TCR-mediated Ca2+ signaling. These include plasma membrane IP3R activated by the ligand IP3, transient receptor potential (TRP) channels that can be operated by DAG and SOCE, adenosine triphosphate (ATP)-responsive purinergic P2 (P2X) receptors, glutamate-mediated N-methyl-d-aspartate activated (NMDA) receptors, and voltage-dependent Ca2+ channels (CaV) that may be regulated through TCR signaling events. The mitochondria (MT) also control cytoplasmic Ca2+ levels. Increase in intracellular Ca2+ results in activation of calmodulin–calcineurin pathway that induces NFAT nuclear translocation and transcription of target genes to direct T cell homeostasis, activation, proliferation, differentiation, apoptosis and survival. Within this complex network of Ca2+ signaling, a model of the reciprocal regulation of CaV1 and ORAI1 in T cells has been proposed. (A) Low-level TCR signaling through interactions with self-antigens (i.e., self-peptides/self-MHC molecules) may result in CaV1 (particularly CaV1.4) activation and Ca2+ influx from outside the cell. This allows for filling of intracellular Ca2+ stores and initiation of a signaling cascade to activate a pro-survival program within the naïve T cell. STIM1 is not activated in this scenario and, consequently, ORAI1 remains closed. (B) Strong TCR signaling through engagement by a foreign peptide-MHC induces the downstream signaling events that result in ER Ca2+ store depletion and STIM1 accumulation in puncta in regions of the ER near the plasma membrane allowing interactions with Ca2+ channels. ORAI1 enhances STIM1 recruitment to the vicinity of CaV1 channels. Here, STIM1 can activate ORAI1 while inhibiting CaV1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 1: The calcium channels in T cells. T cell receptor (TCR) engagement by a peptide-MHC on an antigen presenting cell (APC) induces protein tyrosine kinases (PTKs) to activate phospholipase Cγ1 (PLCγ1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) from plasma membrane phospholipids to generate diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). Elevated levels of IP3 in the cytosol lead to the release of Ca2+ from IP3Rs located in the endoplasmic reticulum (ER). Ca2+ depletion from the ER induces Ca2+ influx from the extracellular space through the plasma membrane channel, ORAI1. Several additional channels also operate during TCR-mediated Ca2+ signaling. These include plasma membrane IP3R activated by the ligand IP3, transient receptor potential (TRP) channels that can be operated by DAG and SOCE, adenosine triphosphate (ATP)-responsive purinergic P2 (P2X) receptors, glutamate-mediated N-methyl-d-aspartate activated (NMDA) receptors, and voltage-dependent Ca2+ channels (CaV) that may be regulated through TCR signaling events. The mitochondria (MT) also control cytoplasmic Ca2+ levels. Increase in intracellular Ca2+ results in activation of calmodulin–calcineurin pathway that induces NFAT nuclear translocation and transcription of target genes to direct T cell homeostasis, activation, proliferation, differentiation, apoptosis and survival. Within this complex network of Ca2+ signaling, a model of the reciprocal regulation of CaV1 and ORAI1 in T cells has been proposed. (A) Low-level TCR signaling through interactions with self-antigens (i.e., self-peptides/self-MHC molecules) may result in CaV1 (particularly CaV1.4) activation and Ca2+ influx from outside the cell. This allows for filling of intracellular Ca2+ stores and initiation of a signaling cascade to activate a pro-survival program within the naïve T cell. STIM1 is not activated in this scenario and, consequently, ORAI1 remains closed. (B) Strong TCR signaling through engagement by a foreign peptide-MHC induces the downstream signaling events that result in ER Ca2+ store depletion and STIM1 accumulation in puncta in regions of the ER near the plasma membrane allowing interactions with Ca2+ channels. ORAI1 enhances STIM1 recruitment to the vicinity of CaV1 channels. Here, STIM1 can activate ORAI1 while inhibiting CaV1.
Mentions: There is increasing evidence in support of relationships between different types of Ca2+ channels, and one such relationship is the one between CaV1.2 and ORAI1 (122, 123). Following Ca2+ store depletion in the ER, STIM1 oligomers form at ER-plasma membrane junctions, thereby allowing the STIM1 CRAC-activating domain (CAD) to interact with the C-terminus of ORAI1 and CaV1.2 channels. STIM1 activates ORAI1 channels, which then open resulting in sustained Ca2+ entry from the extracellular space. On the other hand, STIM1 blocks Ca2+ influx through CaV1.2 and promotes its internalization (122, 123). It may be possible that strong TCR signaling via engagement by a foreign peptide-MHC may lead to this activation of ORAI1 and inhibition of CaV1 channels (Figure 1). In contrast, weaker TCR signaling through engagement with self-antigens might not elicit STIM1 to localize to the plasma membrane, hence activating CaV and blocking ORAI1. Further investigation regarding the interplay between different Ca2+ channel families will greatly advance the field of Ca2+ channel research.

Bottom Line: T cell receptor (TCR) engagement results in depletion of endoplasmic reticulum (ER) Ca(2+) stores and subsequent sustained influx of extracellular Ca(2+) through Ca(2+) release-activated Ca(2+) (CRAC) channels in the plasma membrane.However, several other important Ca(2+) channels that are instrumental in T cell function also exist.In this review, we discuss the role of additional Ca(2+) channel families expressed on the plasma membrane of T cells that likely contribute to Ca(2+) influx following TCR engagement, which include the TRP channels, the NMDA receptors, the P2X receptors, and the IP3 receptors, with a focus on the voltage-dependent Ca(2+) (CaV) channels.

View Article: PubMed Central - PubMed

Affiliation: Michael Smith Laboratories, University of British Columbia , Vancouver, BC , Canada ; Department of Microbiology and Immunology, University of British Columbia , Vancouver, BC , Canada.

ABSTRACT
Elevation of intracellular calcium ion (Ca(2+)) levels is a vital event that regulates T lymphocyte homeostasis, activation, proliferation, differentiation, and apoptosis. The mechanisms that regulate intracellular Ca(2+) signaling in lymphocytes involve tightly controlled concinnity of multiple ion channels, membrane receptors, and signaling molecules. T cell receptor (TCR) engagement results in depletion of endoplasmic reticulum (ER) Ca(2+) stores and subsequent sustained influx of extracellular Ca(2+) through Ca(2+) release-activated Ca(2+) (CRAC) channels in the plasma membrane. This process termed store-operated Ca(2+) entry (SOCE) involves the ER Ca(2+) sensing molecule, STIM1, and a pore-forming plasma membrane protein, ORAI1. However, several other important Ca(2+) channels that are instrumental in T cell function also exist. In this review, we discuss the role of additional Ca(2+) channel families expressed on the plasma membrane of T cells that likely contribute to Ca(2+) influx following TCR engagement, which include the TRP channels, the NMDA receptors, the P2X receptors, and the IP3 receptors, with a focus on the voltage-dependent Ca(2+) (CaV) channels.

No MeSH data available.