Functional importance of the dihydropyridine‐sensitive, yet voltage‐insensitive store‐operated Ca<sup>2+</sup> influx of U937 cells

Willmott, Nicholas J.; Choudhury, Qam; Flower, Roderick J.

doi:10.1016/0014-5793(96)00939-8

Cited by 47 publications

(32 citation statements)

References 24 publications

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“…It should be noted that (ϩ/Ϫ) Bay K 8644 and nifedipine are typically used at 1-300 M on both electrically excitable and nonexcitable cell types. The concentration of DHPs used in these experiments therefore replicated the concentration range of Ca 2ϩ channel modulators applied in other studies (32,33 (34). The addition of the specific Ca 2ϩ chelator, EGTA, prior to stimulation of Jurkat T cells, and human PBTs with ionomycin blocks activation of Erk1/2 demonstrating that one mode of Erk1/2 activation in T lymphocytes is through an increase in intracellular Ca 2ϩ (34).…”

Section: Induction Of Ca 2ϩ Influx In Jurkat T Cell Leukemia Line Andsupporting

confidence: 59%

Identification and Functional Characterization of Voltage-dependent Calcium Channels in T Lymphocytes

Kotturi¹,

Carlow²,

Lee³

et al. 2003

Journal of Biological Chemistry

101

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In T lymphocytes, sustained calcium (Ca 2؉ ) influx through Ca 2؉ channels localized in the plasma membrane is critical for T cell activation and proliferation. Previous studies indicated that voltage-dependent Ca 2؉ channels (VDCCs) play a role in Ca 2؉ mobilization during T lymphocyte activation. However, the role of VDCCs in otherwise nonexcitable cells is still poorly understood. We used RT-PCR to identify a transcript encoding the pore-forming ␣ 1F -subunit of an L-type Ca 2؉ channel in T lymphocytes. Its identity was confirmed by DNA sequencing. To further investigate the contribution of Ca 2؉ influx through VDCCs, we assessed the effects of the 1,4-dihydropyridine L-type Ca 2؉ channel agonist, (؉/؊) Bay K 8644, and antagonist, nifedipine, on the human Jurkat T cell leukemia line, human peripheral blood T lymphocytes and mouse splenocytes. We found that treatment of T lymphocytes with (؉/؊) Bay K 8644 increased intracellular Ca 2؉ and induced the activation of phosphoextracellular-regulated kinase 1/2 (Erk1/2), whereas nifedipine blocked Ca 2؉ influx, the activity of Erk1/2 and nuclear factor of activated T cells (NFAT), interleukin-2 (IL-2) production, and IL-2 receptor expression. Nifedipine also significantly suppressed splenocyte proliferation in an in vitro mixed lymphocyte reaction and the proliferation of male antigen (H-Y)-specific T cell receptor-transgenic CD8 ؉ T cells in transplanted male mice in vivo. Taken together these novel findings indicate that an L-type Ca 2؉ channel plays a significant role in the Ca 2؉ influx pathways mediating T lymphocyte activation and proliferation in vitro and in vivo.

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Section: Induction Of Ca 2ϩ Influx In Jurkat T Cell Leukemia Line Andsupporting

confidence: 59%

Identification and Functional Characterization of Voltage-dependent Calcium Channels in T Lymphocytes

Kotturi¹,

Carlow²,

Lee³

et al. 2003

Journal of Biological Chemistry

101

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“…Young et al (36) showed that BayKϪ, a DHPR agonist, induced an increase in [Ca 2ϩ ] i in Jurkat T cells and concluded that this agonist may interact not only with voltage-gated calcium channels (L-type) but also with the storeoperated calcium channels (calcium release-activated calcium) which are known to be expressed on T cells. A possible capacity of DHPR antagonists to inhibit store-operated calcium channels has also been described in some cells (37,38). Our study did not detect DHPR in murine naive T and Th1 cells; indeed, the staining of these cells with ST-BODIPY-DHP is barely detectable, and we failed to detect a calcium signal in naive T or Th1 cells on exposure to BayKϪ.…”

Section: Discussioncontrasting

confidence: 42%

Dihydropyridine Receptors Are Selective Markers of Th2 Cells and Can Be Targeted to Prevent Th2-Dependent Immunopathological Disorders

Savignac

Gomès

Gallard

et al. 2004

The Journal of Immunology

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Th1 cells that produce IFN-γ are essential in the elimination of intracellular pathogens, and Th2 cells that synthetize IL-4 control the eradication of helminths. However, highly polarized Th1 or Th2 responses may be harmful and even lethal. Thus, the development of strategies to selectively down-modulate Th1 or Th2 responses is of therapeutic importance. Herein, we demonstrate that dihydropyridine receptors (DHPR) are expressed on Th2 and not on Th1 murine cells. By using selective agonists and antagonists of DHPR, we show that DHPR are involved in TCR-dependent calcium response in Th2 cells as well as in IL-4, IL-5, and IL-10 synthesis. Nicardipine, an inhibitor of DHPR, is beneficial in experimental models of Th2-dependent pathologies in rats. It strongly inhibits the Th2-mediated autoimmune glomerulonephritis induced by injecting Brown Norway (BN) rats with heavy metals. This drug also prevents the chronic graft vs host reaction induced by injecting CD4+ T cells from BN rats into (LEW × BN)F1 hybrids. By contrast, treatment with nicardipine has no effect on the Th1-dependent experimental autoimmune encephalomyelitis triggered in LEW rats immunized with myelin. These data indicate that 1) DHPR are a selective marker of Th2 cells, 2) these calcium channels contribute to calcium signaling in Th2 cells, and 3) blockers of these channels are beneficial in the treatment of Th2-mediated pathologies.

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“…4h), to cells resulted in Mn 2ϩ quench of cytosolic fura-2 fluorescence, which was almost completely prevented by pretreat- ing cells with 10 M nicardipine (center traces) for 5 min, indicating that both NO and Tg activate a Ca 2ϩ influx mechanism in glia. It is noteworthy that a previous study also demonstrated nicardipine sensitivity for Tg-induced Ca 2ϩ influx in immature monocytes (Willmott et al, 1996b). There was no significant additive effect on Mn 2ϩ quench of cytosolic fura-2 fluorescence with a combined application of NO and Tg, compared to Tg alone (Fig.…”

Section: Nitric Oxide Induces Ca 2؉ Influx In Glial Cells Which Is Imentioning

confidence: 58%

A Fundamental Role for the Nitric Oxide-G-Kinase Signaling Pathway in Mediating Intercellular Ca²⁺Waves in Glia

2000

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In this study, we highlight a role for the nitric oxide-cGMPdependent protein kinase (NO-G-kinase) signaling pathway in glial intercellular Ca 2ϩ wave initiation and propagation. Addition of the NO donor molsidomine (100-500 M) or puffing aqueous NO onto primary glial cell cultures evoked an increase in [Ca 2ϩ ] i in individual cells and also local intercellular Ca 2ϩ waves, which persisted after removal of extracellular Ca 2ϩ . High concentrations of ryanodine (100-200 M) and antagonists of the NO-G-kinase signaling pathway essentially abrogated the NO-induced increase in [Ca 2ϩ ] i , indicating that NO mobilizes Ca 2ϩ from a ryanodine receptor-linked store, via the NO-G-kinase signaling pathway. Addition of 10 M nicardipine to cells resulted in a slowing of the molsidomine-induced rise in [Ca 2ϩ ] i , and inhibition of Mn 2ϩ quench of cytosolic fura-2 fluorescence mediated by a bolus application of 2 M aqueous NO to cells, indicating that NO also induces Ca 2ϩ influx in glia. Mechanical stress of individual glial cells resulted in an increase in intracellular NO in target and neighboring cells and intercellular Ca 2ϩ waves, which were NO, cGMP, and G-kinase dependent, because incubating cells with nitric oxide synthase, guanylate cyclase, and G-kinase inhibitors, or NO scavengers, reduced ⌬[Ca 2ϩ ] i and the rate of Ca 2ϩ wave propagation in these cultures. Results from this study suggest that NO-Gkinase signaling is coupled to Ca 2ϩ mobilization and influx in glial cells and that this pathway plays a fundamental role in the generation and propagation of intercellular Ca 2ϩ waves in glia. Key words: nitric oxide; glia; calcium waves; mobilization; influx; ryanodine receptors; nitric oxide synthase; DAF-2; phospholipase C; astrocytesIt is becoming increasingly apparent that intercellular Ca 2ϩ waves might be the result of combined contributions of intracellular and extracellular Ca 2ϩ signaling pathways in glial cells. One generally accepted mode of intercellular Ca 2ϩ wave propagation involves the diffusion of Ca 2ϩ mobilizing second messengers, including inositol-1,4,5-trisphosphate (IP 3 ) and Ca 2ϩ , across gap junctions (Nedergaard, 1994;Charles, 1998). Extracellular, gap junction-independent modes of Ca 2ϩ signaling, involving the release of a diffusible messengers, also appear to operate in this particular system however, with ATP release from cells and P 2 receptor-coupled elevation of [Ca 2ϩ ] i having recently been suggested as a likely candidate (Cotrina et al., 1998;Guthrie et al., 1999). There are however other species that may participate as extracellular messengers in glial intercellular Ca 2ϩ waves. There is increasing evidence that the highly diffusible messenger nitric oxide (NO) can induce Ca 2ϩ mobilization in several cell types (Publicover et al., 1993; Willmott et al., 1995a,b,c;Clementi et al., 1996) either via the cGMP-dependent protein kinase (G-kinase)-coupled activation of ADP-ribosyl cyclase, resulting in an increased synthesis of the potent Ca 2ϩ mobilizing agent cyclic ADP-rib...

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Functional importance of the dihydropyridine‐sensitive, yet voltage‐insensitive store‐operated Ca²⁺ influx of U937 cells

Cited by 47 publications

References 24 publications

Identification and Functional Characterization of Voltage-dependent Calcium Channels in T Lymphocytes

Identification and Functional Characterization of Voltage-dependent Calcium Channels in T Lymphocytes

Dihydropyridine Receptors Are Selective Markers of Th2 Cells and Can Be Targeted to Prevent Th2-Dependent Immunopathological Disorders

A Fundamental Role for the Nitric Oxide-G-Kinase Signaling Pathway in Mediating Intercellular Ca²⁺Waves in Glia

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Functional importance of the dihydropyridine‐sensitive, yet voltage‐insensitive store‐operated Ca2+ influx of U937 cells

Cited by 47 publications

References 24 publications

Identification and Functional Characterization of Voltage-dependent Calcium Channels in T Lymphocytes

Identification and Functional Characterization of Voltage-dependent Calcium Channels in T Lymphocytes

Dihydropyridine Receptors Are Selective Markers of Th2 Cells and Can Be Targeted to Prevent Th2-Dependent Immunopathological Disorders

A Fundamental Role for the Nitric Oxide-G-Kinase Signaling Pathway in Mediating Intercellular Ca2+Waves in Glia

Contact Info

Product

Resources

About

Functional importance of the dihydropyridine‐sensitive, yet voltage‐insensitive store‐operated Ca²⁺ influx of U937 cells

A Fundamental Role for the Nitric Oxide-G-Kinase Signaling Pathway in Mediating Intercellular Ca²⁺Waves in Glia