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Placing ion channels into a signaling network of T cells: from maturing thymocytes to healthy T lymphocytes or leukemic T lymphoblasts.

Dobrovinskaya O, Delgado-Enciso I, Quintero-Castro LJ, Best-Aguilera C, Rojas-Sotelo RM, Pottosin I - Biomed Res Int (2015)

Bottom Line: A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially.In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death.In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Research, University of Colima, 28045 Colima, COL, Mexico.

ABSTRACT
T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility.

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Related in: MedlinePlus

Ca2+ influx network in T cells. Channels, marked with asterisks, are overexpressed or present exclusively in T-ALL. Central is activation of CRAC- (Orai1+STIM1) mediated Ca2+ influx. Activation of PLC (e.g., via the T cell receptor) causes cleavage of PIP2 with the production of DAG and soluble IP3; the latter activates IP3-receptor Ca2+ release channels of the endoplasmic reticulum. Ca2+ store depletion is sensed by specialized transmembrane sensors (STIM1), which oligomerize and move to special contact zones of ER with the plasma membrane, where they physically interact with the channel-forming proteins (Orai), forcing them to form active Ca2+ selective channel (CRAC), which mediates Ca2+ influx. Operation of CRAC is further modulated by the activity of other channels, which affects the membrane polarization and intracellular Ca2+. Voltage-independent Ca2+-dependent K+ channels potentiate CRAC-mediated Ca2+ influx, lowering the membrane potential, thus increasing the driving force for Ca2+ uptake. Conversely, channels with a predominant Na+ permeability (TRPM4) cause membrane depolarization and abrogation of the Ca2+ influx. Depending on the channel selectivity high Ca2+ (e.g., TRPV5) or indiscriminate Ca2+/Na+ (e.g., TRPC) as well as (when applicable) on the nature of the feedback (positive or negative, see respective loops) via Ca2+ and on the context (differential ways for the activation of particular ion channel), overall Ca2+ signal can be positively or negatively modulated. An idealized Ca2+ response to a mitogen stimulation, which contains both oscillatory and monotonous increase components, evidencing a feedback regulation via Ca2+, is given as an example. Ways of the channels' activation are summarized below. From the left to the right: Cav (voltage-dependent Ca2+ channels), P2X (purinergic ionotropic receptors), TRP (transient receptor potential channels), Orai-STIM1 (CRAC, Ca2+ release-activated Ca2+ channel), KCa (Ca2+-activated K+ channels), TRESK (TWIK-like spinal cord K+ channel), and CaM (calmodulin).
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fig4: Ca2+ influx network in T cells. Channels, marked with asterisks, are overexpressed or present exclusively in T-ALL. Central is activation of CRAC- (Orai1+STIM1) mediated Ca2+ influx. Activation of PLC (e.g., via the T cell receptor) causes cleavage of PIP2 with the production of DAG and soluble IP3; the latter activates IP3-receptor Ca2+ release channels of the endoplasmic reticulum. Ca2+ store depletion is sensed by specialized transmembrane sensors (STIM1), which oligomerize and move to special contact zones of ER with the plasma membrane, where they physically interact with the channel-forming proteins (Orai), forcing them to form active Ca2+ selective channel (CRAC), which mediates Ca2+ influx. Operation of CRAC is further modulated by the activity of other channels, which affects the membrane polarization and intracellular Ca2+. Voltage-independent Ca2+-dependent K+ channels potentiate CRAC-mediated Ca2+ influx, lowering the membrane potential, thus increasing the driving force for Ca2+ uptake. Conversely, channels with a predominant Na+ permeability (TRPM4) cause membrane depolarization and abrogation of the Ca2+ influx. Depending on the channel selectivity high Ca2+ (e.g., TRPV5) or indiscriminate Ca2+/Na+ (e.g., TRPC) as well as (when applicable) on the nature of the feedback (positive or negative, see respective loops) via Ca2+ and on the context (differential ways for the activation of particular ion channel), overall Ca2+ signal can be positively or negatively modulated. An idealized Ca2+ response to a mitogen stimulation, which contains both oscillatory and monotonous increase components, evidencing a feedback regulation via Ca2+, is given as an example. Ways of the channels' activation are summarized below. From the left to the right: Cav (voltage-dependent Ca2+ channels), P2X (purinergic ionotropic receptors), TRP (transient receptor potential channels), Orai-STIM1 (CRAC, Ca2+ release-activated Ca2+ channel), KCa (Ca2+-activated K+ channels), TRESK (TWIK-like spinal cord K+ channel), and CaM (calmodulin).

Mentions: Ca2+ signaling in T cells differs greatly from those in excitable cells, which mainly rely on the voltage-dependent (depolarization-activated) Ca2+ channels of the plasma membrane. In lymphocytes, contrary to this, Ca2+ rise in cytosol is mediated by the store-operated Ca2+ entry (SOCE), named also CRAC, for Ca2+ release-activated Ca2+ current, that is, Ca2+-selective current of the plasma membrane, activated by the Ca2+ depletion in the ER. It is extremely (factor > 1000) selective for Ca2+ over monovalent cations and has extremely low single channel conductance for Ca2+ (30 fS), which is compensated by a very high channels density (ca. 100 channels/μm2). Due to its intrinsic inward rectification, Ca2+ influx via CRAC is strongly potentiated by membrane hyperpolarization, whereas depolarization reduces Ca2+ entry in lymphocytes [126]. For a long time it was thought that CRAC is mediated by members of TRPC subfamily (see below). Of course, these relatively weakly selective channels alone may not be responsible for a strongly Ca2+-selective CRAC, but now there is also an ample evidence that TRPCs and CRAC are functionally and physically separated [206]. Crucial for molecular identification of CRAC was a study of severe combined immune deficiency (SCID), which was characterized by nonfunctional CRAC in T cells from some patients. In such a way, Orai1 was discovered as a pore-forming protein of CRAC, as single mutation in Orai1 from SCID patients was responsible for a defective CRAC function [207]. Orai does not relate to any known ion channel. In humans, three different isoforms form very similar CRAC channels, but in lymphocytes only Orai1 seems to be of functional importance [208]. Store depletion is communicated to Orai via STIM (stromal interaction molecule) proteins, located in the ER-membrane. In Ca2+ replete stores STIM proteins are randomly distributed at the membrane surface, and store depletion causes oligomerization of STIM in special contact areas with plasma membrane, where cytosolically exposed STIM domain directly interacted with both N- and C termini of Orai1, thus, causing CRAC activation (Figure 4, see also [208] for a recent review). There are two STIM isoforms in T cells, and both are important for CRAC, yet in murine models STIM1 or STIM2 deficiency caused a complete or partial abolishment of CRAC, respectively [209]. CRAC plays a central role in cytokines production, firstly, via Ca2+ activation of the NFAT transcription factor; conversely, it does not play a very significant role in the antibodies production by B cells (see [208] and references therein). Orai1 displays Orai1 displays two-time lower current density in Jurkat lymphoblasts as compared to resting T-cells; no significant difference in STIM1 expression was revealed between these two cellular models [210]. Relatively modest changes in the CRAC expression per se may not underlie changes in Ca2+ signaling in activated and malignant T cells. More likely, differences in the expression and regulation of “partner” K+ channels, especially those activated by intracellular Ca2+ rise, may be more important for the modulation of the CRAC function (Figure 4). As CRAC-mediated Ca2+-influx is inhibited by inflowing Ca2+ [211] and membrane depolarization, its activity may be further modulated by TRPs. TRPs differ greatly not only in the modes of their activation and expression in leukemic T-cells (see below), but also by their Ca2+/Na+ selectivity, hence differentially affecting membrane depolarization and Ca2+ signal. Figure 4 represents possible cross-talks between plasma membrane cation channels, including a feedback, provided by their differential dependence on the cytosolic Ca2+. More scenarios, exploiting TRP and ORAI competition for STIM1, physical interactions, affecting ORAI surface expression and membrane localization, or existence of hybrid SOCE channels are discussed in the recent review by Saul and coworkers (2014) [212].


Placing ion channels into a signaling network of T cells: from maturing thymocytes to healthy T lymphocytes or leukemic T lymphoblasts.

Dobrovinskaya O, Delgado-Enciso I, Quintero-Castro LJ, Best-Aguilera C, Rojas-Sotelo RM, Pottosin I - Biomed Res Int (2015)

Ca2+ influx network in T cells. Channels, marked with asterisks, are overexpressed or present exclusively in T-ALL. Central is activation of CRAC- (Orai1+STIM1) mediated Ca2+ influx. Activation of PLC (e.g., via the T cell receptor) causes cleavage of PIP2 with the production of DAG and soluble IP3; the latter activates IP3-receptor Ca2+ release channels of the endoplasmic reticulum. Ca2+ store depletion is sensed by specialized transmembrane sensors (STIM1), which oligomerize and move to special contact zones of ER with the plasma membrane, where they physically interact with the channel-forming proteins (Orai), forcing them to form active Ca2+ selective channel (CRAC), which mediates Ca2+ influx. Operation of CRAC is further modulated by the activity of other channels, which affects the membrane polarization and intracellular Ca2+. Voltage-independent Ca2+-dependent K+ channels potentiate CRAC-mediated Ca2+ influx, lowering the membrane potential, thus increasing the driving force for Ca2+ uptake. Conversely, channels with a predominant Na+ permeability (TRPM4) cause membrane depolarization and abrogation of the Ca2+ influx. Depending on the channel selectivity high Ca2+ (e.g., TRPV5) or indiscriminate Ca2+/Na+ (e.g., TRPC) as well as (when applicable) on the nature of the feedback (positive or negative, see respective loops) via Ca2+ and on the context (differential ways for the activation of particular ion channel), overall Ca2+ signal can be positively or negatively modulated. An idealized Ca2+ response to a mitogen stimulation, which contains both oscillatory and monotonous increase components, evidencing a feedback regulation via Ca2+, is given as an example. Ways of the channels' activation are summarized below. From the left to the right: Cav (voltage-dependent Ca2+ channels), P2X (purinergic ionotropic receptors), TRP (transient receptor potential channels), Orai-STIM1 (CRAC, Ca2+ release-activated Ca2+ channel), KCa (Ca2+-activated K+ channels), TRESK (TWIK-like spinal cord K+ channel), and CaM (calmodulin).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4383400&req=5

fig4: Ca2+ influx network in T cells. Channels, marked with asterisks, are overexpressed or present exclusively in T-ALL. Central is activation of CRAC- (Orai1+STIM1) mediated Ca2+ influx. Activation of PLC (e.g., via the T cell receptor) causes cleavage of PIP2 with the production of DAG and soluble IP3; the latter activates IP3-receptor Ca2+ release channels of the endoplasmic reticulum. Ca2+ store depletion is sensed by specialized transmembrane sensors (STIM1), which oligomerize and move to special contact zones of ER with the plasma membrane, where they physically interact with the channel-forming proteins (Orai), forcing them to form active Ca2+ selective channel (CRAC), which mediates Ca2+ influx. Operation of CRAC is further modulated by the activity of other channels, which affects the membrane polarization and intracellular Ca2+. Voltage-independent Ca2+-dependent K+ channels potentiate CRAC-mediated Ca2+ influx, lowering the membrane potential, thus increasing the driving force for Ca2+ uptake. Conversely, channels with a predominant Na+ permeability (TRPM4) cause membrane depolarization and abrogation of the Ca2+ influx. Depending on the channel selectivity high Ca2+ (e.g., TRPV5) or indiscriminate Ca2+/Na+ (e.g., TRPC) as well as (when applicable) on the nature of the feedback (positive or negative, see respective loops) via Ca2+ and on the context (differential ways for the activation of particular ion channel), overall Ca2+ signal can be positively or negatively modulated. An idealized Ca2+ response to a mitogen stimulation, which contains both oscillatory and monotonous increase components, evidencing a feedback regulation via Ca2+, is given as an example. Ways of the channels' activation are summarized below. From the left to the right: Cav (voltage-dependent Ca2+ channels), P2X (purinergic ionotropic receptors), TRP (transient receptor potential channels), Orai-STIM1 (CRAC, Ca2+ release-activated Ca2+ channel), KCa (Ca2+-activated K+ channels), TRESK (TWIK-like spinal cord K+ channel), and CaM (calmodulin).
Mentions: Ca2+ signaling in T cells differs greatly from those in excitable cells, which mainly rely on the voltage-dependent (depolarization-activated) Ca2+ channels of the plasma membrane. In lymphocytes, contrary to this, Ca2+ rise in cytosol is mediated by the store-operated Ca2+ entry (SOCE), named also CRAC, for Ca2+ release-activated Ca2+ current, that is, Ca2+-selective current of the plasma membrane, activated by the Ca2+ depletion in the ER. It is extremely (factor > 1000) selective for Ca2+ over monovalent cations and has extremely low single channel conductance for Ca2+ (30 fS), which is compensated by a very high channels density (ca. 100 channels/μm2). Due to its intrinsic inward rectification, Ca2+ influx via CRAC is strongly potentiated by membrane hyperpolarization, whereas depolarization reduces Ca2+ entry in lymphocytes [126]. For a long time it was thought that CRAC is mediated by members of TRPC subfamily (see below). Of course, these relatively weakly selective channels alone may not be responsible for a strongly Ca2+-selective CRAC, but now there is also an ample evidence that TRPCs and CRAC are functionally and physically separated [206]. Crucial for molecular identification of CRAC was a study of severe combined immune deficiency (SCID), which was characterized by nonfunctional CRAC in T cells from some patients. In such a way, Orai1 was discovered as a pore-forming protein of CRAC, as single mutation in Orai1 from SCID patients was responsible for a defective CRAC function [207]. Orai does not relate to any known ion channel. In humans, three different isoforms form very similar CRAC channels, but in lymphocytes only Orai1 seems to be of functional importance [208]. Store depletion is communicated to Orai via STIM (stromal interaction molecule) proteins, located in the ER-membrane. In Ca2+ replete stores STIM proteins are randomly distributed at the membrane surface, and store depletion causes oligomerization of STIM in special contact areas with plasma membrane, where cytosolically exposed STIM domain directly interacted with both N- and C termini of Orai1, thus, causing CRAC activation (Figure 4, see also [208] for a recent review). There are two STIM isoforms in T cells, and both are important for CRAC, yet in murine models STIM1 or STIM2 deficiency caused a complete or partial abolishment of CRAC, respectively [209]. CRAC plays a central role in cytokines production, firstly, via Ca2+ activation of the NFAT transcription factor; conversely, it does not play a very significant role in the antibodies production by B cells (see [208] and references therein). Orai1 displays Orai1 displays two-time lower current density in Jurkat lymphoblasts as compared to resting T-cells; no significant difference in STIM1 expression was revealed between these two cellular models [210]. Relatively modest changes in the CRAC expression per se may not underlie changes in Ca2+ signaling in activated and malignant T cells. More likely, differences in the expression and regulation of “partner” K+ channels, especially those activated by intracellular Ca2+ rise, may be more important for the modulation of the CRAC function (Figure 4). As CRAC-mediated Ca2+-influx is inhibited by inflowing Ca2+ [211] and membrane depolarization, its activity may be further modulated by TRPs. TRPs differ greatly not only in the modes of their activation and expression in leukemic T-cells (see below), but also by their Ca2+/Na+ selectivity, hence differentially affecting membrane depolarization and Ca2+ signal. Figure 4 represents possible cross-talks between plasma membrane cation channels, including a feedback, provided by their differential dependence on the cytosolic Ca2+. More scenarios, exploiting TRP and ORAI competition for STIM1, physical interactions, affecting ORAI surface expression and membrane localization, or existence of hybrid SOCE channels are discussed in the recent review by Saul and coworkers (2014) [212].

Bottom Line: A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially.In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death.In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Research, University of Colima, 28045 Colima, COL, Mexico.

ABSTRACT
T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility.

Show MeSH
Related in: MedlinePlus