Calmodulin Antagonists&amp;rsquo; Binding Sites on Calmodulin

Tanaka, Toshio; Ohmura, Takehisa; Hidaka, Hiroyoshi

doi:10.1159/000137808

Cited by 48 publications

(22 citation statements)

References 21 publications

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“…Involvement of the CaMK signaling pathway in AhR-genomic effects was moreover supported by the fact that W7, a CaM antagonist that prevents Ca 2ϩ /CaM-triggered activation of CaMKs (Tanaka et al, 1983), nearly fully antagonized TCDDmediated up-regulation of CYP1A1 activity and expression. Moreover, knockdown of CaMK expression by RNA interference inhibited CYP1A1 induction in response to TCDD.…”

Section: Discussionmentioning

confidence: 90%

Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

Monteiro

Gilot²,

Ferrec

et al. 2007

Mol Pharmacol

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Section: Discussionmentioning

confidence: 90%

Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

Monteiro

Gilot²,

Ferrec

et al. 2007

Mol Pharmacol

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“…Besides GPV, a number of other receptors, including L-selectin on leukocytes (25) and GPVI on platelets (26), are known to be associated intracellularly with calmodulin and to undergo rapid ectodomain shedding upon treatment with calmodulin inhibitors, such as W13 (27,28). To examine the implication of calmodulin in ADAM17-dependent GPV shedding, platelets were incubated with vehicle or the calmodulin inhibitor W13 (200 M), and GPV surface levels were determined at different time points.…”

Section: Resultsmentioning

confidence: 99%

Evidence for a Role of ADAM17 (TACE) in the Regulation of Platelet Glycoprotein V

Rabie

Strehl

Ludwig

et al. 2005

Journal of Biological Chemistry

102

106

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Glycoprotein V (GPV) is a subunit of the GPIb-IX-V receptor for von Willebrand factor and thrombin and has been shown to modulate platelet responses to the two strongest physiological agonists, thrombin and collagen. Thrombin directly cleaves GPV from the platelet surface, yielding a 69-kDa fragment GPV f1 of unknown function. We show here that a ϳ82-kDa fragment of GPV is shed from the platelet surface upon cellular activation with phorbol 12-myristate 13-acetate or the collagen-related peptide. This shedding was inhibited by the broad range metalloproteinase inhibitor GM6001, the two potent ADAM17 inhibitors GW280264X and TAPI-2, and was absent in mice lacking functional ADAM17 (ADAM17 lacking Zn-binding domain; ADAM17 ⌬Zn/⌬Zn ). Furthermore, we show that recombinant ADAM17 ectodomain efficiently releases GPV from the platelet surface. GPV is known to be associated with the intracellular regulatory protein calmodulin, which has previously been shown to be involved in ADAM17-mediated shedding of L-selectin from the surface of leukocytes. As in these reports, inhibition of calmodulin led to rapid GPV shedding from the platelet surface, a process that was again blocked by GM6001 or ADAM17 inhibitors and that was absent in ADAM17 ⌬Zn/⌬Zn mice. Inhibition of outside-in signaling through GPIIb/IIIa did not significantly affect GPV shedding, excluding an essential role of this pathway for the regulation of ADAM17 activity. These results demonstrate that GPV is cleaved upon agonist-induced platelet activation and show that ADAM17 is the major enzyme mediating this process.Platelet adhesion and aggregation at sites of vascular injury is crucial to limit post-traumatic blood loss but may also harm tissue by occluding diseased vessels. The membrane glycoprotein (GP) 1 Ib-IX-V complex plays a central role in these events in that it mediates the initial platelet tethering to the damaged vessel wall under conditions of elevated shear by interacting with collagen-bound von Willebrand factor (1). The receptor complex consists of four distinct polypeptides, GPIb␣ (M r ϭ 143,000), Ib ␤ (M r ϭ 22,000), V (M r ϭ 83,000), and IX (M r ϭ 20,000), in 1:1:0.5:1 stoichiometry with ϳ25,000 copies per platelet. GPs Ib, V, and IX are structurally related and belong to the family of leucine-rich glycoproteins (2). The receptor complex is associated with the regulatory cytoplasmic protein calmodulin, which is involved in the free Ca 2ϩ uptake upon platelet activation (3), but its exact role in GPIb-IX-V function is unclear.The importance of the GPIb-IX-V complex is emphasized by the study of the Bernard-Soulier syndrome, an inherited bleeding disorder in which the complex is congenitally missing or dysfunctional because of mutations in the genes encoding GPIb or GPIX (2). Likewise, targeted deletion of the GPIb␣ (4) or GPIb␤ (5) genes in mice reproduces the Bernard-Soulier phenotype, as characterized by thrombocytopenia, giant platelets, and massively prolonged bleeding times. Although the essential role of GPIb-IX for normal platelet funct...

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“…To investigate the possible contribution of CaM to NEinduced translocation of cPLA2, the effects of three structurally distinct CaM inhibitors were examined: CLMD (Gietzen et al, 1982), E6-B (Hu et al, 1992) and W-7 (Tanaka et al, 1983). All three inhibitors blocked NE-induced cPLA2 translocation to the nuclear envelope from the cytoplasm and nucleus (Fig.…”

Section: Resultsmentioning

confidence: 99%

CaM kinase IIα mediates norepinephrine-induced translocation of cytosolic phospholipase A2 to the nuclear envelope

Fatima

Yaghini

Ahmed

et al. 2003

Journal of Cell Science

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Several growth factors, hormones and neurotransmitters, including norepinephrine, increase cellular calcium levels, promoting the translocation of cytosolic phospholipase A2 to the nuclear envelope. This study was conducted to investigate the contributions of the calcium-binding protein calmodulin and of calcium—calmodulin-dependent protein kinase II to cytosolic phospholipase A2 translocation to the nuclear envelope elicited by norepinephrine in rabbit aortic smooth-muscle cells. Norepinephrine caused cytosolic phospholipase A2 accumulation around the nuclear envelope as determined from its immunofluorescence; cytosolic phospholipase A2 translocation was blocked by inhibitors of calmodulin and calcium—calmodulin-dependent protein kinase II or calcium—calmodulin-dependent protein kinase IIα antisense oligonucleotide. Calmodulin and calcium—calmodulin-dependent protein kinase II inhibitors did not prevent cytosolic calcium increase but attenuated cytosolic phospholipase A2 phosphorylation caused by norepinephrine or ionomycin. In vascular smooth-muscle cells reversibly permeabilized with β-escin and treated with alkaline phosphatase, norepinephrine failed to cause cytosolic phospholipase A2 phosphorylation and translocation to the nuclear envelope; these effects of norepinephrine were minimized by the phosphatase inhibitor okadaic acid. Recombinant cytosolic phospholipase A2 phosphorylated by purified calcium—calmodulin-dependent protein kinase II, but not unphosphorylated or dephosphorylated cytosolic phospholipase A2, introduced into permeabilized vascular smooth-muscle cells in the absence of calcium accumulated around the nuclear envelope. These data suggest that norepinephrine-induced translocation of cytosolic phospholipase A2 to the nuclear envelope is mediated by its phosphorylation by calcium—calmodulin-dependent protein kinase II and that calcium alone is insufficient for cytosolic phospholipase A2 translocation to the nuclear envelope in rabbit vascular smooth-muscle cells.

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Calmodulin Antagonists’ Binding Sites on Calmodulin

Cited by 48 publications

References 21 publications

Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

Evidence for a Role of ADAM17 (TACE) in the Regulation of Platelet Glycoprotein V

CaM kinase IIα mediates norepinephrine-induced translocation of cytosolic phospholipase A2 to the nuclear envelope

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