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Wei Zhang - One of the best experts on this subject based on the ideXlab platform.
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imperatorin induces vasodilatation possibly via inhibiting voltage dependent Calcium Channel and receptor mediated ca2 influx and release
European Journal of Pharmacology, 2007Co-Authors: Wei Zhang, Yongxiao CaoAbstract:Abstract The purpose of the present study was to investigate the effect of imperatorin on vasodilatation and its possible mechanisms. Isometric tension of rat mesenteric arterial rings was recorded by a myograph system in vitro . The results showed that imperatorin at more than 10 μM concentration-dependently relaxed rat mesenteric arteries pre-contracted by potassium chloride (KCl) and endothelin-1, and human omental arteries pre-contracted by noradrenaline and U46619. Removal of the endothelium did not affect imperatorin-induced relaxant responses, suggesting that the vasodilatation effect is independent of the endothelium. Co-incubation with imperatorin resulted in rightward shift of concentration–response curves of KCl, Calcium chloride (CaCl 2 ) and noradrenaline in a non-parallel manner; 5-hydroxytryptamine (5-HT) concentration–response curves were shifted towards right in a parallel manner by imperatorin 10 and 30 μM, but markedly suppressed by imperatorin 100 μM. These results suggest that the inhibitory effect of imperatorin is mainly via voltage dependent Calcium Channel and possibly receptor operated Calcium Channel. β-adrenoceptor, ATP-sensitive potassium Channel and inwardly rectifying potassium Channel were not involved in the vasodilatation, whereas blockage of Calcium-activated potassium Channel with tetraethylammonium had effect. Furthermore, in Ca 2+ -free medium, imperatorin concentration-dependently depressed the vasoconstrictions derived from noradrenaline and CaCl 2 , and resulted in a decreased contractile response induced by caffeine, indicating a role of inhibiting extracellular Ca 2+ influx and intracellular Ca 2+ release from Ca 2+ store. Taken together, our results suggest that imperatorin induces vasodilatation by possible mechanisms inhibiting voltage dependent Calcium Channel and receptor-mediated Ca 2+ influx and Ca 2+ release. Opening Calcium-activated potassium Channel and competitive antagonism of 5-HT receptors may also contribute to this vasodilatation effect.
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ligustilide induces vasodilatation via inhibiting voltage dependent Calcium Channel and receptor mediated ca2 influx and release
Vascular Pharmacology, 2006Co-Authors: Yongxiao Cao, Wei ZhangAbstract:The purpose of the present study was to investigate the effect of ligustilide on vasodilatation in rat mesenteric artery and the mechanisms responsible for it. Isometric tension of rat mesenteric artery rings was recorded by a sensitive myograph system in vitro. The results showed that ligustilide at concentrations more than 10 mu M relaxed potassium chloride (KCl)-preconstricted rat mesenteric artery in a con centration-dependent manner. The vasodilatation effect of ligustilide was not dependent on endothelium. Ligustilide rightwards shifted concentration-response curves induced by KCl, Calcium chloride (CaCl2), noradrenaline (NA) or 5-hydroxytryptamine (5-HT) in a non-parallel manner. This suggests that the vasodilatation effects were most likely via Voltage-Dependent Calcium Channel (VDCC) and receptor-operated Calcium Channel (ROCC). Propranolol, glibenclamide, tetraethylammonium and barium chloride did not affect the vasodilation induced by ligustilide, showing that beta-adrenoceptor, ATP sensitive potassium Channel, Calcium-activated potassium Channel and inwardly rectifying potassium Channel were not involved in the vasodilatation. Ligustilide concentration-dependently inhibited the vasoconstriction induced by NA or CaCl2 in Ca2+-free medium, indicating that the vasodilatation relates to inhibition of extracellular Ca2+ influx through VDCC and ROCC, and intracellular Ca2+ release from Ca2+ store. Since caffeine-induced contraction was inhibited by ligustilide, inhibition of intracellular Ca2+ released by ligustilide occurred via the ryanodine receptors. Our results suggest that ligustilide induces vasodilatation in rat mesenteric artery by inhibiting the VDCC and ROCC, and receptor-mediated Ca2+ influx and release. (c) 2006 Elsevier Inc. All rights reserved. (Less)
Yongxiao Cao - One of the best experts on this subject based on the ideXlab platform.
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imperatorin induces vasodilatation possibly via inhibiting voltage dependent Calcium Channel and receptor mediated ca2 influx and release
European Journal of Pharmacology, 2007Co-Authors: Wei Zhang, Yongxiao CaoAbstract:Abstract The purpose of the present study was to investigate the effect of imperatorin on vasodilatation and its possible mechanisms. Isometric tension of rat mesenteric arterial rings was recorded by a myograph system in vitro . The results showed that imperatorin at more than 10 μM concentration-dependently relaxed rat mesenteric arteries pre-contracted by potassium chloride (KCl) and endothelin-1, and human omental arteries pre-contracted by noradrenaline and U46619. Removal of the endothelium did not affect imperatorin-induced relaxant responses, suggesting that the vasodilatation effect is independent of the endothelium. Co-incubation with imperatorin resulted in rightward shift of concentration–response curves of KCl, Calcium chloride (CaCl 2 ) and noradrenaline in a non-parallel manner; 5-hydroxytryptamine (5-HT) concentration–response curves were shifted towards right in a parallel manner by imperatorin 10 and 30 μM, but markedly suppressed by imperatorin 100 μM. These results suggest that the inhibitory effect of imperatorin is mainly via voltage dependent Calcium Channel and possibly receptor operated Calcium Channel. β-adrenoceptor, ATP-sensitive potassium Channel and inwardly rectifying potassium Channel were not involved in the vasodilatation, whereas blockage of Calcium-activated potassium Channel with tetraethylammonium had effect. Furthermore, in Ca 2+ -free medium, imperatorin concentration-dependently depressed the vasoconstrictions derived from noradrenaline and CaCl 2 , and resulted in a decreased contractile response induced by caffeine, indicating a role of inhibiting extracellular Ca 2+ influx and intracellular Ca 2+ release from Ca 2+ store. Taken together, our results suggest that imperatorin induces vasodilatation by possible mechanisms inhibiting voltage dependent Calcium Channel and receptor-mediated Ca 2+ influx and Ca 2+ release. Opening Calcium-activated potassium Channel and competitive antagonism of 5-HT receptors may also contribute to this vasodilatation effect.
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ligustilide induces vasodilatation via inhibiting voltage dependent Calcium Channel and receptor mediated ca2 influx and release
Vascular Pharmacology, 2006Co-Authors: Yongxiao Cao, Wei ZhangAbstract:The purpose of the present study was to investigate the effect of ligustilide on vasodilatation in rat mesenteric artery and the mechanisms responsible for it. Isometric tension of rat mesenteric artery rings was recorded by a sensitive myograph system in vitro. The results showed that ligustilide at concentrations more than 10 mu M relaxed potassium chloride (KCl)-preconstricted rat mesenteric artery in a con centration-dependent manner. The vasodilatation effect of ligustilide was not dependent on endothelium. Ligustilide rightwards shifted concentration-response curves induced by KCl, Calcium chloride (CaCl2), noradrenaline (NA) or 5-hydroxytryptamine (5-HT) in a non-parallel manner. This suggests that the vasodilatation effects were most likely via Voltage-Dependent Calcium Channel (VDCC) and receptor-operated Calcium Channel (ROCC). Propranolol, glibenclamide, tetraethylammonium and barium chloride did not affect the vasodilation induced by ligustilide, showing that beta-adrenoceptor, ATP sensitive potassium Channel, Calcium-activated potassium Channel and inwardly rectifying potassium Channel were not involved in the vasodilatation. Ligustilide concentration-dependently inhibited the vasoconstriction induced by NA or CaCl2 in Ca2+-free medium, indicating that the vasodilatation relates to inhibition of extracellular Ca2+ influx through VDCC and ROCC, and intracellular Ca2+ release from Ca2+ store. Since caffeine-induced contraction was inhibited by ligustilide, inhibition of intracellular Ca2+ released by ligustilide occurred via the ryanodine receptors. Our results suggest that ligustilide induces vasodilatation in rat mesenteric artery by inhibiting the VDCC and ROCC, and receptor-mediated Ca2+ influx and release. (c) 2006 Elsevier Inc. All rights reserved. (Less)
Henry M Colecraft - One of the best experts on this subject based on the ideXlab platform.
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bio inspired voltage dependent Calcium Channel blockers
Nature Communications, 2013Co-Authors: Tingting Yang, Ming Chen, Kun Fang, Henry M ColecraftAbstract:Ca(2+) influx via Voltage-Dependent CaV1/CaV2 Channels couples electrical signals to biological responses in excitable cells. CaV1/CaV2 Channel blockers have broad biotechnological and therapeutic applications. Here we report a general method for developing novel genetically encoded Calcium Channel blockers inspired by Rem, a small G-protein that constitutively inhibits CaV1/CaV2 Channels. We show that diverse cytosolic proteins (CaVβ, 14-3-3, calmodulin and CaMKII) that bind pore-forming α1-subunits can be converted into Calcium Channel blockers with tunable selectivity, kinetics and potency, simply by anchoring them to the plasma membrane. We term this method 'Channel inactivation induced by membrane-tethering of an associated protein' (ChIMP). ChIMP is potentially extendable to small-molecule drug discovery, as engineering FK506-binding protein into intracellular sites within CaV1.2-α1C permits heterodimerization-initiated Channel inhibition with rapamycin. The results reveal a universal method for developing novel Calcium Channel blockers that may be extended to develop probes for a broad cohort of unrelated ion Channels.
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bio inspired voltage dependent Calcium Channel blockers
Biophysical Journal, 2013Co-Authors: Tingting Yang, Ming Chen, Kun Fang, Henry M ColecraftAbstract:Blocking Voltage-Dependent CaV1/CaV2 Channels is a prevailing or potential therapy for myriad diseases ranging from hypertension to Parkinson's disease, but a major limitation is lack of selective small-molecule inhibitors for distinct CaV1/CaV2 Channels. Here, we report a general bio-inspired approach towards developing novel CaV1/CaV2 Channel blockers (CCBs). We discovered that different proteins (CaVβ, 14-3-3, camodulin, and calmodulin-dependent protein kinase II) that bind to spatially distinct regions of pore-forming α1-subunit intracellular loops can be converted into CCBs, with tuneable selectivity and potency, simply by their anchoring to the plasma membrane. The principle is extendable to small molecules— engineering FKBP into specific sites within CaV1.2 α1C intracellular loops permitted heterodimerization-initiated Channel inhibition with rapamycin (Fig). The results reveal a universal method for developing novel genetically-encoded and small-molecule CCBs.View Large Image | View Hi-Res Image | Download PowerPoint Slide
Hideyuki Yamawaki - One of the best experts on this subject based on the ideXlab platform.
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a current perspective of canstatin a fragment of type iv collagen alpha 2 chain
Journal of Pharmacological Sciences, 2019Co-Authors: Muneyoshi Okada, Hideyuki YamawakiAbstract:Type IV collagen is a main component of basement membrane extracellular matrix. Canstatin, a non-collagenous C-terminal fragment of type IV collagen α2 chain, was firstly identified as an endogenous anti-angiogenic and anti-tumor factor, which also has an anti-lymphangiogenic effect. Then, canstatin has been widely investigated as a novel target molecule for cancer therapy. The anti-angiogenic effect of canstatin may be also useful for the treatment of ocular neovascularization. Recently, we have demonstrated that canstatin, which is abundantly expressed in the heart tissue, exerts various biological activities in cardiac cells. In rat H9c2 cardiomyoblasts, canstatin inhibits isoproterenol- or hypoxia-induced apoptosis. Canstatin plays an important role in modulating Voltage-Dependent Calcium Channel activity in rat cardiomyocytes. Canstatin also regulates various biological functions in rat cardiac fibroblasts and myofibroblasts. The expression of canstatin decreases in the infarcted area after myocardial infarction. This review focuses on a current perspective for the roles of canstatin in tumorigenesis, ocular neovascularization and cardiac pathology.
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A current perspective of canstatin, a fragment of type IV collagen alpha 2 chain
Elsevier, 2019Co-Authors: Muneyoshi Okada, Hideyuki YamawakiAbstract:Type IV collagen is a main component of basement membrane extracellular matrix. Canstatin, a non-collagenous C-terminal fragment of type IV collagen α2 chain, was firstly identified as an endogenous anti-angiogenic and anti-tumor factor, which also has an anti-lymphangiogenic effect. Then, canstatin has been widely investigated as a novel target molecule for cancer therapy. The anti-angiogenic effect of canstatin may be also useful for the treatment of ocular neovascularization. Recently, we have demonstrated that canstatin, which is abundantly expressed in the heart tissue, exerts various biological activities in cardiac cells. In rat H9c2 cardiomyoblasts, canstatin inhibits isoproterenol- or hypoxia-induced apoptosis. Canstatin plays an important role in modulating Voltage-Dependent Calcium Channel activity in rat cardiomyocytes. Canstatin also regulates various biological functions in rat cardiac fibroblasts and myofibroblasts. The expression of canstatin decreases in the infarcted area after myocardial infarction. This review focuses on a current perspective for the roles of canstatin in tumorigenesis, ocular neovascularization and cardiac pathology. Keywords: Anti-tumor effect, Canstatin, Fibroblasts, Cytoprotective effect, Myocardial infarctio
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FULL PAPER Pharmacology
2015Co-Authors: Jumpei Yasuda, Lila Takada, Yuka Kajiwara, Muneyosi Okada, Hideyuki YamawakiAbstract:ABSTRACT. Endogenous fragments of extracellular matrix are known to possess various biological effects. Levels of endostatin, a fragment of collagen type XVIII, increase in certain cardiac diseases, such as cardiac hypertrophy and myocardial infarction. However, the influence of endostatin on cardiac contraction has not been clarified. In the present study, we investigated the effects of endostatin on bradykinin-induced atrial contraction. Isometric contractile force of mouse isolated left atria induced by electrical current pulse was measured. Voltage-Dependent Calcium current of guinea pig ventricular myocytes was measured by a whole-cell patch-clamp technique. Endostatin (100–1,000 ng/ml) alone treatment had no influence on left atrial contraction. On the other hand, pretreatment with endostatin (300 ng/ml) significantly inhibited bradykinin (1 µM)-induced contraction and Voltage-Dependent Calcium current. These data suggest that endostatin may decrease bradykinin-induced cardiac contraction perhaps through the inhibition of Voltage-Dependent Calcium Channel. KEY WORDS: bradykinin, bradykinin type 2 receptor, endostatin, Voltage-Dependent Calcium Channel doi: 10.1292/jvms.15-0200; J. Vet. Med. Sci. 77(11): 1391–1395, 2015 Angiotensin converting enzyme (ACE) inhibitors are widely used for the treatment of hypertension and heart fail-ure. Because ACE catalyzes the degradation of bradykinin, prolonged ACE inhibitor treatment increases bradykinin level [17]. Bradykinin binds to two kinds of receptors, B
Maureen W. Mcenery - One of the best experts on this subject based on the ideXlab platform.
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immunological characterization of t type voltage dependent Calcium Channel cav3 1 alpha1g and cav3 3 alpha1i isoforms reveal differences in their localization expression and neural development
Neuroscience, 2003Co-Authors: A M R Yunker, A H Sharp, S Sundarraj, V Ranganathan, T D Copeland, Maureen W. MceneryAbstract:Low voltage-activated Calcium Channels (LVAs; “T-type”) modulate normal neuronal electrophysiological properties such as neuronal pacemaker activity and rebound burst firing, and may be important anti-epileptic targets. Proteomic analyses of available alpha1G/CaV3.1 and alpha1I/CaV3.3 sequences suggest numerous potential isoforms, with specific alpha1G/CaV3.1 or alpha1I/CaV3.3 domains postulated to be conserved among isoforms of each T-type Channel subtype. This information was used to generate affinity-purified anti-peptide antibodies against sequences unique to alpha1G/CaV3.1 or alpha1I/CaV3.3, and these antibodies were used to compare and contrast alpha1G/CaV3.1 and alpha1I/CaV3.3 protein expression by western blotting and immunohistochemistry. Each antibody reacted with appropriately sized recombinant protein in HEK-293 cells. Regional and developmental differences in alpha1G/CaV3.1 and alpha1I/CaV3.3 protein expression were observed when the antibodies were used to probe regional brain dissections prepared from perinatal mice and adult rodents and humans. Mouse forebrain alpha1G/CaV3.1 (∼240 kDa) was smaller than cerebellar (∼260 kDa) alpha1G/CaV3.1, and expression of both proteins increased during perinatal development. In contrast, mouse midbrain and diencephalic tissues evidenced an alpha1I/CaV3.3 immunoreactive doublet (∼230 kDa and ∼190 kDa), whereas other brain regions only expressed the small alpha1I/CaV3.3 isoform. A unique large alpha1I/CaV3.3 isoform (∼260 kDa) was expressed at birth and eventually decreased, concomitant with the appearance and gradual increase of the small alpha1I/CaV3.3 isoform. Immunohistochemistry supported the conclusion that LVAs are expressed in a regional manner, as cerebellum strongly expressed alpha1G/CaV3.1, and olfactory bulb and midbrain contained robust alpha1I/CaV3.3 immunoreactivity. Finally, strong alpha1I/CaV3.3, but not alpha1G/CaV3.1, immunoreactivity was observed in brain and spinal cord by embryonic day 14 in situ. Taken together, these data provide an anatomical and biochemical basis for interpreting LVA heterogeneity and offer evidence of developmental regulation of LVA isoform expression.
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biochemical and anatomical evidence for specialized voltage dependent Calcium Channel γ isoform expression in the epileptic and ataxic mouse stargazer
Neuroscience, 2001Co-Authors: A H Sharp, A M R Yunker, S Sundarraj, T D Copeland, J L Black, Stefan J Dubel, J P Shen, Maureen W. MceneryAbstract:Abstract Inherited forms of ataxia and absence seizures in mice have been linked to defects in Voltage-Dependent Calcium Channel subunits. However, a correlation between the sites of neuronal dysfunction and the impact of the primary lesion upon Calcium Channel subunit expression or function has not been clearly established. For example, the mutation in stargazer mice has pleiotropic consequences including synaptic alterations in cerebellar granule cells, hippocampal CA3/mossy fibers, and cortical neurons in layer V that, presumably, lead to ataxia and seizures. Genetic analysis of stargazer mice determined that the defective gene encodes a protein expressed in brain (γ2) with limited homology to the skeletal muscle L-type Calcium Channel γ1 subunit. Although additional γ isoforms have been subsequently identified primarily in neural tissue, little was known about the proteins they encode. Therefore, this study explored the distribution and biochemical properties of γ2 and other γ isoforms in wild-type and stargazer brain. We cloned human γ2, γ3, and γ4 isoforms, produced specific anti-peptide antibodies to γ isoforms and characterized both heterologously expressed and endogenous γ. We identified regional specificity in the expression of γ isoforms by western analysis and immunohistochemistry. We report for the first time that the mutation in the stargazer gene resulted in the loss of γ2 protein. Furthermore, no compensatory changes in the expression of γ3 or γ4 protein were evident in stargazer brain. In contrast to other Voltage-Dependent Calcium Channel subunits, γ immunostaining was striking in that it was primarily detected in regions highly enriched in excitatory glutamatergic synapses and faintly detected in cell bodies, suggesting a role for γ in synaptic functions. Sites of known synaptic dysfunction in stargazer (the hippocampal CA3 region, dentate gyrus, and cerebellar molecular layer) were revealed as relying primarily upon γ2, as total γ isoform expression was dramatically decreased in these regions. Electron microscopy localized anti-γ antibody immunostaining to dendritic structures of hippocampal mossy fiber synapses, with enrichment at postsynaptic densities. To assess the association of native γ with Voltage-Dependent Calcium Channel or α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits, γ isoforms (γ2, γ3 and γ4) were detergent solubilized from mouse forebrain. Antibodies against a highly conserved C-terminal epitope present in γ2, γ3 and γ4 immunoprecipitated Voltage-Dependent Calcium Channel subunits (α1B), providing the first in vivo evidence that γ and Voltage-Dependent Calcium Channels form stable complexes. Furthermore, both anti-γ2 antibodies and anti-α1B antibodies independently immunoprecipitated the AMPA receptor subunit, GluR1, from mouse forebrain homogenates. In summary, loss of γ2 immunoreactivity in stargazer is precisely localized so as to contribute to previously characterized synaptic defects. The data in this paper provide compelling evidence that γ isoforms form complexes in vivo with Voltage-Dependent Calcium Channels as well as AMPA receptors, are selectively and differentially expressed in neuronal processes, and localize primarily to dendritic structures in the hippocampal mossy fiber region.
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the association of endogenous go alpha with the purified omega conotoxin gvia receptor
Journal of Biological Chemistry, 1994Co-Authors: Maureen W. Mcenery, Adele M Snowman, S SnyderAbstract:Abstract Modulation of the neuronal omega-conotoxin GVIA-sensitive N-type Voltage-Dependent Calcium Channel (VDCC) by neurotransmitters and guanine nucleotides suggests a dynamic interaction between activated G-protein alpha subunits and the N-type VDCC. Our previous report on the purification of the N-type VDCC (McEnery, M. W., Snowman, A. M., Sharp, A. H., Adams, M. E., and Snyder, S. H. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 11095-11099), has led us to investigate a possible association of CTXR with an endogenous G alpha subunit. The addition of the G-protein activator AIF4- modulated the 125I-CTX binding characteristics of the solubilized CTXR. Further immunological analyses employing G alpha subunit-specific antibodies to monitor the cofractionation of G alpha with 125I-CTX binding activity throughout the purification procedure indicate the selective recovery of Go alpha in the purified CTXR preparation, as neither Gs alpha, Gi alpha, nor G beta gamma could be detected. Furthermore, Go alpha associated with CTXR acted as a substrate for pertussis toxin-dependent ADP-ribosylation only upon the addition of exogenous G beta gamma subunits. These results strongly indicate a high affinity complex between an activated Go alpha and CTXR maintained throughout biochemical purification of the 125I-CTX receptor.
