The suppressive effects of YM-58483/BTP-2, a store-operated Ca2+ entry blocker, on inflammatory mediator release in vitro and airway responses in vivo

Ohga, Keiko; Takezawa, Ryuichi; Yoshino, Taiji; Yamada, Toshimitsu; Shimizu, Yoshiyuki; Ishikawa, Jun

doi:10.1016/j.pupt.2007.09.003

Cited by 47 publications

(30 citation statements)

References 45 publications

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“…Importantly, unlike other TRP inhibitors, SK&F 96365 and 2-aminoethyldiphenylborate, BTP2 is selective to TRP channels and does not affect Ca 2ϩ handling by mitochondria or ER, or K ϩ channels or voltage-dependent Ca 2ϩ channels (25)(26)(27). Pharmacological profiles of BTP2 have been investigated in vitro and in vivo to evaluate its potential as a therapeutic anti-asthma drug (28). However, BTP2 failed to show subtype selectivity among members of the TRPC family, inhibiting both TRPC3 and TRPC5 (27).…”

Section: Canonical Transient Receptor Potential (Trpc) Channels Contrmentioning

confidence: 99%

Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

Kiyonaka

Kato

Nishida

et al. 2009

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

342

318

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Canonical transient receptor potential (TRPC) channels control influxes of Ca 2؉ and other cations that induce diverse cellular processes upon stimulation of plasma membrane receptors coupled to phospholipase C (PLC). Invention of subtype-specific inhibitors for TRPCs is crucial for distinction of respective TRPC channels that play particular physiological roles in native systems. Here, we identify a pyrazole compound (Pyr3), which selectively inhibits TRPC3 channels. Structure-function relationship studies of pyrazole compounds showed that the trichloroacrylic amide group is important for the TRPC3 selectivity of Pyr3. Electrophysiological and photoaffinity labeling experiments reveal a direct action of Pyr3 on the TRPC3 protein. In DT40 B lymphocytes, Pyr3 potently eliminated the Ca 2؉ influx-dependent PLC translocation to the plasma membrane and late oscillatory phase of B cell receptorinduced Ca 2؉ response. Moreover, Pyr3 attenuated activation of nuclear factor of activated T cells, a Ca 2؉ -dependent transcription factor, and hypertrophic growth in rat neonatal cardiomyocytes, and in vivo pressure overload-induced cardiac hypertrophy in mice. These findings on important roles of native TRPC3 channels are strikingly consistent with previous genetic studies. Thus, the TRPC3-selective inhibitor Pyr3 is a powerful tool to study in vivo function of TRPC3, suggesting a pharmaceutical potential of Pyr3 in treatments of TRPC3-related diseases such as cardiac hypertrophy.Ca 2ϩ signaling ͉ pyrazole compounds ͉ TRPC channels ͉ TRPC3

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Section: Canonical Transient Receptor Potential (Trpc) Channels Contrmentioning

confidence: 99%

Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

Kiyonaka

Kato

Nishida

et al. 2009

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

342

318

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“…In this study, BTP2 was shown to inhibit not only production of IL-2, but also of IL-5 and IFN-g, and T-cell proliferation. Both antigen-induced histamine release from an IgE-primed rat basophilic leukemia cell line (RBL-2H3) and IL-5 and IL-13 production in human peripheral blood cells were blocked by BTP2 with an IC 50 in the low nanomolar range [106]. BTP2 suppressed ovalbumin-induced airway hyperresponsiveness and bronchoconstriction by inhibiting the I CRAC -induced inflammatory mediator and cytokine production [106].…”

Section: Btp2 To Examine the Physiological Function And Therapeutic Usementioning

confidence: 99%

“…Both antigen-induced histamine release from an IgE-primed rat basophilic leukemia cell line (RBL-2H3) and IL-5 and IL-13 production in human peripheral blood cells were blocked by BTP2 with an IC 50 in the low nanomolar range [106]. BTP2 suppressed ovalbumin-induced airway hyperresponsiveness and bronchoconstriction by inhibiting the I CRAC -induced inflammatory mediator and cytokine production [106]. In addition, BTP2 has been shown to prevent antigen-induced airway eosinophil infiltration and late-phase asthmatic responses, probably by inhibition of I CRACinduced production of cytokines and inflammatory mediators in Th2 cells [107].…”

Section: Btp2 To Examine the Physiological Function And Therapeutic Usementioning

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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“…Experimental and clinical studies have demonstrated that voltage-gated Ca 2ϩ channel blockers have no obvious effects on the regulation of airway hyperresponsiveness (13); in contrast, SOC channel blockers have been shown to be effective in attenuating airway hyperresponsiveness in ovalbumin-sensitized guinea pigs (20 (9,16). The underlying mechanisms that transfer the signal of ER store depletion to SOC channels in the PM are not understood.…”

mentioning

confidence: 99%

Role of STIM1/Orai1-mediated store-operated Ca²⁺ entry in airway smooth muscle cell proliferation

Zou

Gao

Geng

et al. 2011

Journal of Applied Physiology

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store, where it interacts with Orai1, the molecular component of SOC channels, and brings about SOCE. STIM1 and Orai1 have been proved to mediate SOCE of ASMCs. In this study, we investigated whether STIM1/Orai1-mediated SOCE is involved in rat ASMC proliferation. We found that SOCE was upregulated during ASMC proliferation accompanied by a mild increase of STIM1 and a significant increase of Orai1 mRNA expression, whereas the proliferation of ASMCs was partially inhibited by the SOC channel blockers SKF-96365, NiCl2, and BTP-2. Suppressing the mRNA expression of STIM1 or Orai1 with specific short hairpin RNA resulted in the attenuation of SOCE and ASMC proliferation. Moreover, after knockdown of STIM1 or Orai1, the SOC channel blocker SKF-96365 had no inhibitory effect on the proliferation of ASMCs anymore. These results suggested that STIM1/Orai1-mediated SOCE is involved in ASMC proliferation. calcium channels; stromal interaction molecule-1 DYSFUNCTION of airway smooth muscle plays a key role in the pathogenesis of airway hyperresponsiveness (21 (9, 16). The underlying mechanisms that transfer the signal of ER store depletion to SOC channels in the PM are not understood. An RNA inhibitorbased screening approach revealed a membrane-spanning protein, stromal interaction molecule (STIM)1, to be required for the activation of SOC channels (17). STIM1 proteins are dispersedly located on the ER membrane in quiescence; upon depletion of ER Ca 2ϩ stores, they oligomerize and translocate to junctions adjacent to the PM, where they organize Orai1 into clusters and open these channels to bring about SOCE (5, 27). Besides Orai1, transient receptor potential canonical (TRPC) channels have also been suggested to be molecular candidates of SOC channels, and an interaction between STIM1 and TRPC has been demonstrated (1, 19). Knockdown of STIM1 or Orai1 with specific small interfering RNA sequences resulted in a reduction of SOCE in response to store depletion by histamine or thapsigargin in human ASMCs, indicating that STIM1 and Orai1 are important contributors to SOCE in ASMCs (23,24). Moreover, Ca 2ϩ influx through SOC channels has been proposed to be involved in the proliferation of ASMCs (28). In rat aorta vascular SMCs, both the protein expression of STIM1 and Orai1 and the activity of SOC channels were upregulated in synthetic proliferating cells compared with quiescent cells; knockdown of STIM1 inhibited the proliferation and migration of vascular SMCs (4,25). These data indicate that STIM1 and Orai1 may play a role in the regulation of ASMC proliferation. In the present study, we examined SOCE and STIM1/ Orai1 mRNA expression in quiescent and proliferating ASMCs and the effect of suppressing STIM1 or Orai1 expression on SOCE and ASMC proliferation.

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The suppressive effects of YM-58483/BTP-2, a store-operated Ca2+ entry blocker, on inflammatory mediator release in vitro and airway responses in vivo

Cited by 47 publications

References 45 publications

Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

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

Role of STIM1/Orai1-mediated store-operated Ca²⁺ entry in airway smooth muscle cell proliferation

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The suppressive effects of YM-58483/BTP-2, a store-operated Ca2+ entry blocker, on inflammatory mediator release in vitro and airway responses in vivo

Cited by 47 publications

References 45 publications

Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

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

Role of STIM1/Orai1-mediated store-operated Ca2+ entry in airway smooth muscle cell proliferation

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Role of STIM1/Orai1-mediated store-operated Ca²⁺ entry in airway smooth muscle cell proliferation