Characterization of YM-58483/BTP2, a novel store-operated Ca2+ entry blocker, on T cell-mediated immune responses in vivo

Ohga, Keiko; Takezawa, Ryuichi; Arakida, Yasuhito; Shimizu, Yoshiyuki; Ishikawa, Jun

doi:10.1016/j.intimp.2008.08.016

Cited by 63 publications

(42 citation statements)

References 41 publications

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“…136 Thus, the altered pore geometry of mutant Orai1 channels and 2-APB-gated Orai3 channels makes effect of BTP2 on a mouse graft-vs.-host disease model and in sheep blood cell-induced delayed type hypersensitivity reaction in mice, attributed to its inhibition of T-cell activation. 124 These data are consistent with the role of CRAC channels in the T-cell activation process. BTP2 also inhibited antigen induced degranulation and cytokine secretion in murine mast cells.…”

Section: -Apb Analogues Dpb162-ae and Dpb163-aesupporting

confidence: 86%

Molecular pharmacology of store-operated CRAC channels

Jairaman

Prakriya

2013

Channels

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Section: -Apb Analogues Dpb162-ae and Dpb163-aesupporting

confidence: 86%

Molecular pharmacology of store-operated CRAC channels

Jairaman

Prakriya

2013

Channels

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“…BTP2 is an enticing therapeutic candidate, as it inhibits SOCe without altering baseline intracellular Ca 2+ levels, suggesting that it does not affect unstimulated cells. Furthermore, mice can tolerate a dosage of up to 30 mg/kg without any systemic toxicity (39). Although BTP2 inhibits the function of CRAC, TRPC3, and TRPC5 channels, while activating TRPM4 channels (56-58), using Stim1 ΔEC mice, we reveal STIM1-mediated Ca 2+ entry as the critical contributor to LPS-induced EC activation and necrotic cell death, the key events in the initiation of ALI.…”

Section: Store-operated Camentioning

confidence: 79%

“…Recent evidence from in vitro studies and our Stim1 ΔEC mouse model data suggest that LPSinduced vascular permeability and lung inflammation are partly driven by a pulmonary endothelial NOX2/STIM1 pathway. To examine the therapeutic potential of this mechanism, we tested the highly effective small-molecule Ca 2+ channel blocker BTP2 in an animal model of sepsis (39). Wild-type mice were administered LPS (1 mg/kg; i.p.)…”

Section: Figurementioning

confidence: 99%

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Gandhirajan¹,

Meng²,

et al. 2013

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During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca 2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPSmediated Ca 2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca 2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca 2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1 -/-mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca 2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.

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“…Thus, BTP2 might be a candidate therapeutic agent for bronchial asthma [107]. In a graft-versus-host disease, BTP2 not only reduced the number of donor T-cells, especially donor CD8 + T cells, but also suppressed donor anti-host cytotoxic T-lymphocyte activity and IFN-g, suggesting its therapeutical use in autoimmune diseases, such as autoimmune hepatitis and rheumatoid arthritis [108]. BTP2 reduced the superoxide anion production in human neutrophils but did not significantly affect phagocytosis, intraphagosomal radical production or bacterial killing, suggesting a possible application in downregulation of neutrophils in chronic inflammatory disease without compromising antibacterial host defence [109].…”

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confidence: 99%

Pharmacology of ORAI channels as a tool to understand their physiological functions

Bogeski

Alansary

et al. 2010

Expert Review of Clinical Pharmacology

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A u t h o r P r o o fwww.expert-reviews.com 3 ReviewPharmacology of ORAI channels STIM proteinsIn humans, the ER Ca 2+ -sensor STIM has two homologs: STIM1 and STIM2. Whereas STIM1 is activated in IP 3 -induced signaling pathways, STIM2 seems to play a role for Ca 2+ entry under resting conditions. Both, STIM1 and STIM2 have one transmembrane segment and span mainly the ER membrane, although a portion of the protein is also found in the plasma membrane (Figure 1). The luminal N-terminal domain features an EF hand as a Ca 2+ binding pocket and a sterile a-motif (SAM) domain. The C-terminal domain contains an ezrin-radixin-myosin-like domain, including two coiled-coil regions, a serine/proline-rich region and a polylysine-rich region [26,33,34].The IP 3 -induced decrease in luminal Ca 2+ concentration leads to a dissociation of Ca 2+ bound to the EF hand of STIM1 (EC 50 = 200-600 µM) [35]. Subsequently, STIM1 molecules oligomerize and then aggregate in clusters (puncta), localized 10-25 nm beneath the plasma membrane, and activate CRAC channels [31,36,37]. Recent studies started to assign structural features of STIM1 to distinct actions during CRAC channel activation [38,39]. Baba et al. stated that puncta formation requires the N-terminal SAM domain and that the coiled-coil region and a serine/threonine-rich region mediate the constitutive movement of STIM. In another study, the C-terminal coiled-coil region was found to be crucial for puncta formation and the serine/ proline-rich region was found to be important for the correct targeting of the STIM1 cluster to the plasma membrane, whereas the polylysine-rich region is characterized by a supportive but not essential function for the targeting [39]. Smyth et al. reported that I CRAC suppression during mitosis is based on phosphorylation of Ser486 and Ser668 and, possibly, other sites in STIM1 [40].In contrast to STIM1, STIM2 does not seem to redistribute within the ER after store depletion but may rather be precoupled to plasma membrane CRAC channels [25]. One cytosolic inhibitor of precoupling STIM2/ORAI1 is Ca 2+ calmodulin [25]. STIM2 activates CRAC ion channels already at smaller decreases of Ca 2+ concentration in the ER (EC 50 of the EF hand for Ca 2+ is 500 µM), which leads to a basal Ca 2+ influx into the cell [27,28]. STIM1 and STIM2 appear to have distinct properties; whereas STIM2-mediated Ca 2+ influx seems to sustain the basal intracellular Ca 2+ concentration, IP 3 -induced STIM1-mediated Ca 2+ elevations lead to the activation of a plethora of cellular responses. A recent study utilizing STIM2-knockout mice demonstrated that STIM2 is also a key player for Ca 2+ signal transduction during hypoxic neurological damage [41].Before being described as a major component of the SOCE machinery [16,18,42], STIM1 was identified as a tumor suppressor [43][44][45] located at the plasma membrane (PM) [46]. The latter finding is rather controversial. Several studies failed to confirm cell surface expression of N-terminally tagged STIM1 when rather bulky tags were...

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Characterization of YM-58483/BTP2, a novel store-operated Ca2+ entry blocker, on T cell-mediated immune responses in vivo

Cited by 63 publications

References 41 publications

Molecular pharmacology of store-operated CRAC channels

Molecular pharmacology of store-operated CRAC channels

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Pharmacology of ORAI channels as a tool to understand their physiological functions

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