Abstract：
BACKGROUND AND PURPOSE:(-)-Englerin A (EA) is a potent cytotoxic agent against renal carcinoma cells. It achieves its effects by activation of transient receptor potential canonical (TRPC)4/TRPC1 heteromeric channels. It is also an agonist at channels formed by the related protein, TRPC5. Here, we sought an EA analogue, which might enable a better understanding of these effects of EA. EXPERIMENTAL APPROACH:An EA analogue, A54, was synthesized by chemical elaboration of EA. The effects of EA and A54 on the activity of human TRPC4 or TRPC5 channels overexpressed on A498 and HEK 293 cells were investigated, firstly, by measuring intracellular Ca2+ and, secondly, current using whole-cell patch clamp recordings. KEY RESULTS:A54 had weak or no agonist activity at endogenous TRPC4/TRPC1 channels in A498 cells or TRPC4 or TRPC5 homomeric channels overexpressed in HEK 293 cells. A54 strongly inhibited EA-mediated activation of TRPC4/TRPC1 or TRPC5 and weakly inhibited activation of TRPC4. Studies of TRPC5 showed that A54 shifted the EA concentration-response curve to the right without changing its slope, consistent with competitive antagonism. In contrast, Gd3+ -activated TRPC5 or sphingosine-1-phosphate-activated TRPC4 channels were not inhibited but potentiated by A54. A54 did not activate TRPC3 channels or affect the activation of these channels by the agonist 1-oleoyl-2-acetyl-sn-glycerol. CONCLUSIONS AND IMPLICATIONS:This study has revealed a new tool compound for EA and TRPC1/4/5 channel research, which could be useful for characterizing endogenous TRPC1/4/5 channels and understanding EA-binding sites and their physiological relevance.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Rubaiy HN,Seitz T,Hahn S,Choidas A,Habenberger P,Klebl B,Dinkel K,Nussbaumer P,Waldmann H,Christmann M,Beech DJdoi
10.1111/bph.14128subject
Has Abstractpub_date
2018-03-01 00:00:00pages
830-839issue
5eissn
0007-1188issn
1476-5381journal_volume
175pub_type
杂志文章abstract：:1. We examined the effect of the sulphonylurea glimepiride on three types of recombinant ATP-sensitive potassium (K(ATP)) channels. 2. K(ATP) channels share a common pore-forming subunit, Kir6.2, which associates with different sulphonylurea receptor isoforms (SUR1 in beta-cells, SUR2A in heart and SUR2B in smooth mus...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704062
更新日期：2001-05-01 00:00:00
abstract：:1. The effects of fenoverine, an antispasmodic drug, have been studied on the Ca2+ channel currents of isolated cells from rat portal vein and pregnant myometrium by the patch-clamp technique (whole-cell configuration). 2. Fenoverine inhibited both fast and slow Ca2+ channel currents in a concentration-dependent manne...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1991.tb12386.x
更新日期：1991-09-01 00:00:00
abstract：:1. Antilaminin IgG decreased the dF/dt of mouse isolated atria and inhibited the mechanical effect of acetylcholine in a non-competitive fashion. 2. Inhibitors of nicotinic and muscarinic cholinoceptors impaired the negative inotropic action of antilaminin IgG in mouse isolated atria. Hemicholinium and tetrodotoxin al...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1989.tb11964.x
更新日期：1989-06-01 00:00:00
abstract：:1. Bepridil (BPD) is a pharmacological compound able to bind to the Ca2+ sensor protein troponin C (TnC), which triggers skeletal muscle contraction upon Ca2+-binding. BPD can thereby modulate the Ca2+-affinity of this protein. 2. The Ca2+-sensitizing action of bepridil was investigated on slow and fast isoforms of Tn...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702820
更新日期：1999-10-01 00:00:00
abstract：:1. Daily i.p. administration, for eight days, of the cholinesterase inhibitor disulfoton to rats produced mild to moderate signs of intoxication (tremors, incontinence and diarrhoea) but no deaths.2. Segments of ileum taken from the treated rats were subsensitive to carbachol but the vas deferens and the uterus did no...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1973.tb08350.x
更新日期：1973-07-01 00:00:00
abstract：:The neuroprotective drug riluzole has multiple effects on cellular signaling. We found that riluzole rapidly and reversibly inhibited spontaneous Ca2+ oscillations in both immortalized GnRH-secreting hypothalamic neurons (GT1 cells) and in the prolactin and growth-hormone-secreting GH3 cell line. At lower concentratio...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705491
更新日期：2003-11-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Some neurosteroids, notably 3alpha-hydroxysteroids, positively modulate GABA(A) receptors, but sulphated steroids negatively modulate these receptors. Recently, other lipophilic amphiphiles have been suggested to positively modulate GABA receptors. We examined whether there was similarity among t...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2010.00679.x
更新日期：2010-05-01 00:00:00
abstract：:1. The neurotransmitters involved in NANC relaxation and their possible interactions were investigated in mouse isolated stomach, recording the motor responses as changes of endoluminal pressure from whole organ. 2. Field stimulation produced tetrodotoxin-sensitive, frequency-dependent, biphasic responses: rapid trans...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705431
更新日期：2003-09-01 00:00:00
abstract：:1. Mice pretreated intraperitoneally for 2 days with delta-9-tetrahydrocannabinol (delta-9-THC) at a dose of 20 mg kg-1 day-1 and then challenged intravenously with this drug, 24 h after the second pretreatment, showed a 6 fold tolerance to the hypothermic effect of delta-9-THC. This pretreatment also induced toleranc...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1993.tb13989.x
更新日期：1993-12-01 00:00:00
abstract：:1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1994.tb14775.x
更新日期：1994-02-01 00:00:00
abstract：:1. Comparison of the rank order of potency of the natural prostanoids prostaglandin E2 (PGE2), PGD2, PGF2 alpha and carbaprostacyclin in stimulating cyclic AMP in Jurkat cells is consistent with the presence of an EP receptor. 2. Lack of responsiveness to the EP1/EP3 selective agonist, sulprostone, and the EP2 agonist...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1995.tb15030.x
更新日期：1995-08-01 00:00:00
abstract：BACKGROUND AND PURPOSE:GoSlo-SR compounds are efficacious BK (KCa 1.1) channel openers, but little is known about their mechanism of action or effect on bladder contractility. We examined the effects of two closely related compounds on BK currents and bladder contractions. EXPERIMENTAL APPROACH:A combination of electr...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.13085
更新日期：2015-05-01 00:00:00
abstract：:In vitro preparations of rabbit heart were made from which measurements of effective refractory period (ERP), atrio-Hisian (A-H) and His-Purkinje (H-P) conduction times could be obtained, analogous to electrophysiological measurements customarily carried out in vivo. Intracellular potentials also were recorded from th...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1983.tb10007.x
更新日期：1983-07-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Catechol-O-methyltransferase (COMT) metabolizes compounds containing catechol structures and has two forms: soluble (S-COMT) and membrane-bound (MB-COMT). Here we report the generation of a mouse line that expresses MB-COMT but not S-COMT. We compared the effects of deleting S-COMT only or both C...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2009.00494.x
更新日期：2009-12-01 00:00:00
abstract：:1 Urocortin is a vasodilator peptide related to corticotrophin-releasing factor, which may protect endothelial function during coronary ischemia-reperfusion (I-R). The aim of this study was to study the mechanisms of this protective effect. 2 Hearts from Sprague-Dawley rats were isolated and perfused at constant flow ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706208
更新日期：2005-06-01 00:00:00
abstract：:Using recently available selective agonists and antagonists we have examined further our postulate (Apperley et al., 1980) that 5-hydroxytryptamine (5-HT) mediates contraction of dog saphenous vein via a different 5-HT receptor type from that in the rabbit aorta. In the rabbit isolated aorta, ketanserin and spiperone ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1985.tb08948.x
更新日期：1985-11-01 00:00:00
abstract：:1. The effects of chronic dietary supplementation with omega 3 polyunsaturated fatty acids on endothelium-dependent relaxations were examined in isolated coronary microvessels of the pig. 2. Animals were maintained for four weeks with or without dietary supplementation of purified eicosapentaenoic acid (3.5 g daily) a...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1988.tb11755.x
更新日期：1988-12-01 00:00:00
abstract：BACKGROUND AND PURPOSE:The endocannabinoid system and the cannabinoid CB(1) receptor have been identified in human sperm, and it is well known that endocannabinoids have pronounced adverse effects on male and female reproduction. In order to elucidate further the pathophysiological role of the endocannabinoid system in...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2009.00570.x
更新日期：2010-02-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Sublesional osteoporosis predisposes individuals with spinal cord injury (SCI) to an increased risk of low-trauma fracture. The aim of the present work was to investigate the effect of treatment with resveratrol (RES) on sublesional bone loss in spinal cord-injured rats. EXPERIMENTAL APPROACH:Co...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.12301
更新日期：2013-10-01 00:00:00
abstract：BACKGROUND AND PURPOSE:The two longest C-termini of the purinergic P2X receptors occur in the P2X2 and P2X7 receptors and are thought to interact with multiple cytoplasmic proteins, among which are members of the cytoskeleton, including microtubules. In this work we asked whether disrupting the microtubule cytoskeleton...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2011.01254.x
更新日期：2011-07-01 00:00:00
abstract：:Despite progression in anticancer drug development and improvements in the clinical utilization of therapies, current treatment regimes are still dependent upon the use of systemic antiproliferative cytotoxic agents. Although these agents are unquestionably potent, their efficacy is limited by toxicity towards 'normal...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1038/sj.bjp.0707657
更新日期：2008-04-01 00:00:00
abstract：:Chlorisondamine (CHL) blocks behavioural responses to nicotine for several weeks or months in rats. Persistent blockade has also been demonstrated ex vivo, in assays of nicotine-evoked striatal dopamine release. Central administration of [3H]-CHL leads to long-term retention of radiolabel in nigrostriatal dopaminergic...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702215
更新日期：1998-11-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5-HT) transporter (SERT) in mediating these effects. EXPERIMENTAL APPROACH:Hippocampal long-term potentiation (LTP) and neurogenesi...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.14760
更新日期：2019-09-01 00:00:00
abstract：:1. The aim of the present study was to explore the contribution of adrenergic, sensory and nitrergic innervations to the inhibitory effects of the beta2-adrenoceptor agonist clenbuterol on responses to electrical field stimulation (EFS, 200 mA, 0.3 ms, 1-16 Hz, for 30 s, at 1 min interval) in rat mesenteric artery seg...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0701856
更新日期：1998-06-01 00:00:00
abstract：:1 The activation of tachykinin NK(1) receptors in the rat spinal cord produced a transient drop in arterial blood pressure followed by a more prolonged pressor effect which is mediated by the stimulation of the sympatho-adrenal system. This study aims at characterizing the spinal mechanism of that initial hypotension ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704813
更新日期：2002-08-01 00:00:00
abstract：:Transient expression in COS-7 cells of the recombinant human 5-hydroxytryptamine (5-HT) h5-HT4(c) receptor isoform led to constitutive activity of the receptor. The 5-HT4 receptor antagonist 2-(cis-3,5-dimethylpiperidino)ethyl 4-amino-5-chloro-2-methoxybenzoate (ML10375) at 1 microM completely abolished the 5-HT (1 mi...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702163
更新日期：1998-10-01 00:00:00
abstract：:1 We have investigated the effects of platelet-activating factor (PAF), an endogenous mediator of inflammation, on ion transport and prostaglandin synthesis in the human isolated colon. 2 Application of PAF to the serosal surface of human colonic mucosa induced a marked, concentration-dependent increase in ion transpo...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0701602
更新日期：1998-01-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normal...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.12169
更新日期：2013-07-01 00:00:00
abstract：:1. The chemically novel acetohydroxamic acids, BW A4C, BW A137C and BW A797C, are potent inhibitors of the synthesis of leukotriene B4 (LTB4) from arachidonic acid by human leucocyte homogenates: the concentrations required for 50% inhibition (IC50) were 0.1 microM, 0.8 microM and 0.5 microM respectively. Inhibition w...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1988.tb11557.x
更新日期：1988-06-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Mitochondria possess their own source of cAMP, that is, soluble adenylyl cyclase (sAC). Activation or expression of mitochondrial sAC promotes mitochondrial function. Oestrogen receptor signalling plays an essential role in the regulation of mitochondrial function. Here we aimed to determine whet...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.14455
更新日期：2018-10-01 00:00:00
