Non-voltage-gated L-type Ca2+ Channels in Human T Cells

Stokes, Leanne; Gordon, John; Grafton, Gillian

doi:10.1074/jbc.m401481200

Cited by 65 publications

(31 citation statements)

References 50 publications

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“…Altogether, these observations suggest that depolarization is unlikely to play a major role in opening T cell Cav channels. Alternatively, Cav1 channels could be regulated in a voltage-independent manner as previously suggested for human Jurkat cells (12), where other TCR-triggered signaling events such as phosphorylation would induce opening. This hypothesis is strongly supported by the earlier surprising findings showing that Cav1.3 channels can be activated at voltages of approximately Ϫ60 mV under physiological calcium concentrations (41,42).…”

Section: Impairment Of Tcr-mediated Calcium͞nfat Pathway Activation Imentioning

confidence: 99%

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Badou¹,

Jha²,

Matza³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

146

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Calcium ion is a universal signaling intermediate, which is known to control various biological processes. In excitable cells, voltagegated calcium channels (Cav) are the major route of calcium entry and regulate multiple functions such as contraction, neurotransmitter release, and gene transcription. Here we show that T lymphocytes, which are nonexcitable cells, express both regulatory ␤ and pore-forming Cav1 ␣1 subunits of Cav channels, and we provide genetic evidence for a critical role of the Cav ␤3 and Cav ␤4 regulatory subunits in T lymphocyte function. Cav ␤-deficient T lymphocytes fail to acquire normal functions, and they display impairment in the T cell receptor-mediated calcium response, nuclear factor of activated T cells activation, and cytokine production. In addition, unlike in excitable cells, our data suggest a minimal physiological role for depolarization in Cav channel opening in T cells. T cell receptor stimulation induces only a small depolarization of T cells, and artificial depolarization of T cells using KCl does not lead to calcium entry. These observations suggest that the Cav channels expressed by T cells have adopted novel regulation͞gating mechanisms.C alcium ion plays critical and specific roles in various T cell functions, including activation, differentiation, proliferation, and cytokine production (1, 2). In T lymphocytes, ligation of the T cell receptor (TCR) by antigen leads to the release of calcium from intracellular stores, triggering the calcium release-activated calcium current (3), and a potential candidate for calcium release-activated calcium current channel was recently reported (4-6). But the complexity of the calcium response in T cells suggests the expression of more than one plasma membrane calcium channel. Although it is established that, in excitable cells, Cav channels constitute the major route of calcium entry (7), the functional presence of the Cav1 channels in T lymphocytes has been suggested (8-13) but has remained controversial because of the lack of a reliable and specific loss-of-function approach.Cav ␤ subunits are cytoplasmic proteins that strongly regulate Cav channels through direct interaction with pore-forming ␣1 subunits (14-17). The ␤ subunits are also critical for assembly of the channel complex (18), correct plasma membrane targeting (19,20), and stimulation of channel activity (21). A number of potential ␣1-␤ combinations are likely to form a Cav channel complex (22), and, among these, the ␤4 and ␤3 subunits are key subunits that associate with Cav1 channels (23-25).A spontaneous mutation named lethargic, which arose in the mouse inbred strain BALB͞cGn in 1962, is recognizable in homozygous mice at 2 weeks of age by the onset of ataxia, seizures, and lethargic behavior (26,27). These mice also exhibit a generalized immunological disorder including defective cell-mediated immune responses (28). It has been reported, using a positional cloning approach, that this syndrome was the result of a mutation of the Cav ␤4 subunit gene (29). This mutatio...

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Section: Impairment Of Tcr-mediated Calcium͞nfat Pathway Activation Imentioning

confidence: 99%

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Badou¹,

Jha²,

Matza³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

146

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“…Classical L-type calcium channels are voltage-gated and most typically express in excitable cells. Several reports have documented, however, the presence of non-voltage-dependent L-type calcium channels in various non-excitable cells such as T and B cells, or in mouse and human macrophages (36,42,43). Patch clamp experiments were performed in the J774A.1 macrophages used in this study, but no L-type calcium currents could be recorded (data not shown), suggesting that L-type like calcium channels in the J774A.1 macrophages do not respond to a voltage activation.…”

Section: J774a1 Cells and Cd11bmentioning

confidence: 99%

Bordetella Adenylate Cyclase Toxin Promotes Calcium Entry into Both CD11b+ and CD11b− Cells through cAMP-dependent L-type-like Calcium Channels

Martı́n

Gómez-Bilbao²,

Ostolaza

2010

Journal of Biological Chemistry

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Adenylate cyclase toxin (ACT), a 200 kDa protein, is an essential virulence factor for Bordetella pertussis, the bacterium that causes whooping cough. ACT is a member of the pore-forming RTX (repeats-in-toxin) family of proteins that share a characteristic calcium-binding motif of Gly-and Asp-rich nonapeptide repeats and a marked cytolytic or cytotoxic activity. In addition, ACT exhibits a distinctive feature: it has an N-terminal calmodulin-dependent adenylate cyclase domain. Translocation of this domain into the host cytoplasm results in uncontrolled production of cAMP, and it has classically been assumed that this surge in cAMP is the basis for the toxin-mediated killing. Several members of the RTX family of toxins, including ACT, have been shown to induce intracellular calcium increases, through different mechanisms. We show here that ACT stimulates a raft-mediated calcium influx, through its cAMP production activity, that activates PKA, which in turn activates calcium channels with L-type properties. This process is shown to occur both in CD11b ؉ and CD11b ؊ cells, suggesting a common mechanism, independent of the toxin receptor. We also show that this ACTinduced calcium influx does not correlate with the toxin-induced cytotoxicity.Adenylate cyclase toxin (ACT) 3 is a crucial virulence factor secreted by Bordetella pertussis, the bacterium that causes whooping cough (1). ACT is a single polypeptide chain of 1706 amino acid residues that consists of an adenylate cyclase domain corresponding to the 400 N-terminal residues (AC domain) and a characteristic RTX (Repeats in Toxin) hemolysin domain comprising the C-terminal 1306 residues (2). The hemolysin domain consists in turn of a hydrophobic (channelforming) domain (residues 500 -700), an acylation domain (residues 800 -1000), and a characteristic glycine/aspartaterich repeats domain (residues 1000 -1600), typically present in the members of the RTX family of proteins to which ACT belongs (3, 4). Binding of calcium to these repeats induces conformational changes in the toxin molecule (5, 6) necessary for the toxin functionality. The RTX moiety insertion into cellular membranes is necessary to mediate the translocation of the AC catalytic domain into the cytosol of host cells, myeloid phagocytes that express the integrin receptor CD11b/CD18, and upon activation by cellular calmodulin, it catalyzes an uncontrolled conversion of ATP into cAMP, a process often referred to as "intoxication" (7,8). The RTX domain accounts as well for the hemolytic activity of ACT (9 -11). This toxin can form cation-selective pores in cell membranes independent of translocation, thereby perturbing ion homeostasis. This pore-forming activity has been reported to contribute to the cytotoxic action of ACT by cooperating with cAMP in promoting cell death (12, 13). More recently, Fiser et al. (14) have reported a third activity of ACT, which involves a sustained rise of [Ca 2ϩ ] i promoted by membrane translocation of the AC domain (14).Several members of the RTX family of toxins have...

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“…Several studies support that DHPR are involved in calcium responses of non-excitable cells, including B lymphocytes (21), NK cells (19), dendritic cells (20), naive T cells (24), Th2 cells (18,28), and epithelial cells (45,46). It has been shown that signaling through the B cell receptor was coupled to a guanylate cyclase/cGMP-dependent pathway that controlled DHPR-dependent calcium entry (21).…”

Section: Discussionmentioning

confidence: 99%

“…Here we have shown that in Th2 lymphocytes DHPR antagonization by nicardipine reduced cGMP-mediated calcium response, suggesting a role for DHPR in cGMP signaling. Although the structure of DHPR has not been completely elucidated in lymphocytes, DHPR had been related to the ␣1 calcium channel subunit in B cells (21) as well as in Th2 cells (18) and human T cells (24). In excitable cells, the NO/cGMP/PKG pathway is known to activate or repress DHPR-dependent calcium currents depending upon the cell type (47,48).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that in Th2 cells TCR engagement involved dihydropyridine receptor (DHPR)-dependent calcium inflow (18). DHPR were also detected in other immune cells including natural killer (NK) cells (19), dendritic cells (20), B lymphocytes (21,22), and naive T cells (23,24). In B cells, DHPR-dependent [Ca 2ϩ ] i increase subsequent to antigen receptor stimulation was shown to be mediated by cGMP (21).…”

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confidence: 99%

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The cGMP/Protein Kinase G Pathway Contributes to Dihydropyridine-sensitive Calcium Response and Cytokine Production in TH2 Lymphocytes

Gomès

Savignac

Cabral

et al. 2006

Journal of Biological Chemistry

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Th2 lymphocytes differ from other CD4؉ T lymphocytes not only by their effector tasks but also by their T cell receptor (TCR)-dependent signaling pathways. We previously showed that dihydropyridine receptors (DHPR) involved in TCR-induced calcium inflow were selectively expressed in Th2 cells. In this report, we studied whether cGMP-dependent protein kinase G (PKG) activation was implicated in the regulation of DHPR-dependent calcium response and cytokine production in Th2 lymphocytes. The contribution of cGMP in Th2 signaling was supported by the following results: 1) TCR activation elicited cGMP production, which triggered calcium increase responsible for nuclear factor of activated T cell translocation and Il4 gene expression; 2) guanylate cyclase activation by nitric oxide donors increased intracellular cGMP concentration and induced calcium inflow and IL-4 production; 3) reciprocally, guanylate cyclase inhibition reduced calcium response and Th2 cytokine production associated with TCR activation. In addition, DHPR blockade abolished cGMP-induced [Ca 2؉ ] i increase, indicating that TCR-induced DHP-sensitive calcium inflow is dependent on cGMP in Th2 cells. Th2 lymphocytes from PKG1-deficient mice displayed impaired calcium signaling and IL-4 production, as did wild-type Th2 cells treated with PKG inhibitors. Altogether, our data indicate that, in Th2 cells, cGMP is produced upon TCR engagement and activates PKG, which controls DHP-sensitive calcium inflow and Th2 cytokine production.

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Non-voltage-gated L-type Ca2+ Channels in Human T Cells

Cited by 65 publications

References 50 publications

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Bordetella Adenylate Cyclase Toxin Promotes Calcium Entry into Both CD11b+ and CD11b− Cells through cAMP-dependent L-type-like Calcium Channels

The cGMP/Protein Kinase G Pathway Contributes to Dihydropyridine-sensitive Calcium Response and Cytokine Production in TH2 Lymphocytes

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