共查询到20条相似文献,搜索用时 31 毫秒
1.
Corzo G Papp F Varga Z Barraza O Espino-Solis PG Rodríguez de la Vega RC Gaspar R Panyi G Possani LD 《Biochemical pharmacology》2008,76(9):1142-1154
A novel potassium channel blocker peptide was purified from the venom of the scorpion Centruroides suffusus suffusus by high-performance liquid chromatography and its amino acid sequence was completed by Edman degradation and mass spectrometry analysis. It contains 38 amino acid residues with a molecular weight of 4000.3 Da, tightly folded by three disulfide bridges. This peptide, named Css20, was shown to block preferentially the currents of the voltage-dependent K+-channels Kv1.2 and Kv1.3. It did not affect several other ion channels tested at 10 nM concentration. Concentration-response curves of Css20 yielded an IC50 of 1.3 and 7.2 nM for Kv1.2- and Kv1.3-channels, respectively. Interestingly, despite the similar affinities for the two channels the association and dissociation rates of the toxin were much slower for Kv1.2, implying that different interactions may be involved in binding to the two channel types; an implication further supported by in silico docking analyses. Based on the primary structure of Css20, the systematic nomenclature proposed for this toxin is α-KTx 2.13. 相似文献
2.
Despite the great variability of the conus peptides characterized until now only relatively few have been identified that interact with K+ channels. κM-conotoxin RIIIK (κM-RIIIK) is a 24 amino acid peptide from Conus radiatus, which is structurally similar to μ-conotoxin GIIIA, a peptide known to block specifically skeletal muscle Na+ channels. Recently, it has been shown that κM-RIIIK does not interact with Na+ channels, but inhibits Shaker potassium channels expressed in Xenopus oocytes. It was demonstrated that κM-RIIIK binds to the pore region of Shaker channels and a teleost homologue of the Shaker channel TSha1 was identified as a high affinity target of the toxin. In contrast the mammalian Shaker-homologues Kv1.1, Kv1.3, Kv1.4 are not affected by the toxin. In this study the activity of κM-RIIIK on other mammalian Kv1 K+ channels expressed in Xenopus oocytes was investigated. We demonstrate that κM-conotoxin RIIIK up to 5 μM exhibits no significant effect on Kv1.5 and Kv1.6 mediated currents, but the human Kv1.2 K+ channel is blocked by this peptide. The binding of κM-RIIIK to Kv1.2 channels is state dependent with an IC50 for the closed state of about 200 nM and for the open state of about 400 nM at a test potential of 0 mV. κM-conotoxin RIIIK is the first conotoxin described to block human Kv1.2 potassium channels. 相似文献
3.
Chenhu Qin Xuhua Yang Zheng Zuo Liuting Yang Fan Yang Zhijian Cao Zongyun Chen Yingliang Wu 《Toxins》2021,13(9)
Thermally processed Buthus martensii Karsch scorpions are a traditional Chinese medical material for treating various diseases. However, their pharmacological foundation remains unclear. Here, a new degraded peptide of scorpion toxin was identified in Chinese scorpion medicinal material by proteomics. It was named BmK86-P1 and has six conserved cysteine residues. Homology modeling and circular dichroism spectra experiments revealed that BmK86-P1 not only contained representative disulfide bond-stabilized α-helical and β-sheet motifs but also showed remarkable stability at test temperatures from 20–95 °C. Electrophysiology experiments indicated that BmK86-P1 was a highly potent and selective inhibitor of the hKv1.2 channel with IC50 values of 28.5 ± 6.3 nM. Structural and functional dissection revealed that two residues of BmK86-P1 (i.e., Lys19 and Ile21) were the key residues that interacted with the hKv1.2 channel. In addition, channel chimeras and mutagenesis experiments revealed that three amino acids (i.e., Gln357, Val381 and Thr383) of the hKv1.2 channel were responsible for BmK86-P1 selectivity. This research uncovered a new bioactive peptide from traditional Chinese scorpion medicinal material that has desirable thermostability and Kv1.2 channel-specific activity, which strongly suggests that thermally processed scorpions are novel peptide resources for new drug discovery for the Kv1.2 channel-related ataxia and epilepsy diseases. 相似文献
4.
Martentoxin (MarTX), a 37-residue peptide purified from the venom of East-Asian scorpion (Buthus martensi Karsch), was capable of blocking large-conductance Ca2+-activated K+ (BK) channels. Here, we report an effective expression and purification approach for this toxin. The cDNA encoding martentoxin was expressed by the prokaryotic expression system pGEX-4T-3 which was added an enterokinase cleavage site by PCR. The fusion protein (GST-rMarTX) was digested by enterokinase to release hetero-expressed toxin and further purified via reverse-phase HPLC. The molecular weight of the hetero-expressed rMarTX was 4059.06 Da, which is identical to that of the natural peptide isolated from scorpion venom. Functional characterization through whole-cell patch clamp showed that rMarTX selectively and potently inhibited the currents of neuronal BK channels (α + β4) (IC50 = 186 nM), partly inhibited mKv1.3, but hardly having any significant effect on hKv4.2 and hKv3.1a even at 10 μM. Successful expression of martentoxin lays basis for further studies of structure-function relationship underlying martentoxin or other potassium-channel specific blockers. 相似文献
5.
Song Han Youtian Hu Ruhong ZhangHong Yi Jingjing WeiYingliang Wu Zhijian CaoWenxin Li Xiaohua He 《Toxicon》2011,57(2):348-355
Scorpion toxins are useful in the structure-function research of ion channels and valuable resources for drug design. The Kv1.3 channel is an important pharmacological target for the therapy of T cell-mediated autoimmune diseases, and many toxin peptides targeting Kv1.3 have been identified as good drug candidates in recent years. In this study, a novel toxin gene ImKTx88 was isolated from the venom of the scorpion Isometrus maculates through the construction of the cDNA library method, and the recombinant toxin peptide was purified and characterized physiologically. The mature peptide of ImKTx88 contained 39 amino acid residues including six cysteines and was predicted to be a new member of α-KTx scorpion family by sequence analysis. The electrophysiological experiments further indicated that the rImKTx88 peptide had a novel pharmacological profile: it inhibited Kv1.3 channel current with an IC50 of 91 ± 42 pM, and exhibited very good selectivity for Kv1.3 over Kv1.1 (4200-fold) and Kv1.2 (93000-fold) channels, respectively. All these results suggested that, as a new selective Kv1.3 channel blocker, the ImKTx88 peptide may serve as a potential drug candidate in the therapy of autoimmune diseases. 相似文献
6.
Jingzhaotoxin-XIII (JZTX-XIII), a 35 residue polypeptide, with the ability to inhibit voltage-dependent potassium channels in the shab (Kv2) and shal (Kv4) subfamilies, was purified from the venom of the Chinese tarantula Chilobrachys jingzhao. Electrophysiological recordings carried out in Xenopus laevis oocytes showed that JZTX-XIII acted as gating modifier of voltage-dependent K+ channels which inhibited the Kv2.1 channel and Kv4.1 channel, with the IC50 value of 0.47 μM and 1.17 μM, respectively. JZTX-XIII shares high sequence similarity with gating modifier toxins inhibiting a wide variety of ion channels including Nav1.5 subtype, but it showed no Nav1.5 channel activity. Structure-function analysis indicates that the acidic residues of Glu10 and Glu17 in JZTX-XIII might be responsible for the loss of the Nav1.5 channel inhibitory potency for JZTX-XIII. 相似文献
7.
Erythromycin administration has been associated with a prolongation of cardiac repolarization in certain clinical settings.
This could be due to blockade of voltage-dependent K+ channels in the human heart. For this reason we examined the effects of erythromycin on a rapidly activating delayed rectifier
K+ channel (Kv1.5) cloned from human heart and stably expressed in human embryonic kidney cells. When examined using the whole-cell
patch clamp technique, erythromycin (100 μM) blocked Kv1.5 current in a time-dependent manner but required prolonged exposure
to do so. However, when we examined Kv1.5 current using inside-out macropatches, erythromycin applied to the cytoplasmic surface
rapidly (within 1-2 min) inhibited Kv1.5 current with an IC50 value of 2.6 x 10-5M (1.7 - 3.9 x 10-5M, 95% C.L.). The main effect of erythromycin was to accelerate the rate of Kv1.5 current decay thereby reducing the current
at the end of a prolonged voltage-clamp pulse. Erythromycin also blocked Kv1.5 current in both a voltage- and frequency-dependent
manner but had little effect on the activation kinetics, deactivation kinetics, or the steady-state inactivation properties
of Kv1.5. These data suggest that erythromycin acts as a blocker of an activated state of the Kv1.5 channel and that it may
access its binding site from the intracellular face of the channel. This study is the first to examine the effects of erythromycin
on a cloned human cardiac K+ channel. It is concluded that erythromycin blocks Kv1.5 at clinically relevant concentrations. Blockade of voltage-dependent
K+ channels in the heart could contribute to the alterations in cardiac repolarization that have been observed with erythromycin.
Received: 22 November 1996 / Accepted: 26 February 1997 相似文献
8.
Shunyi Zhu Bin Gao Meichun Deng Yuzhe Yuan Lan Luo Yucheng Xiao Jan Tytgat 《Biochemical pharmacology》2010,80(8):1296-1302
The design of animal toxins with high target selectivity has long been a goal in protein engineering. Based on evolutionary relationship between the Drosophila antifungal defensin (drosomycin) and scorpion depressant Na+ channel toxins, we exploited a strategy to create a novel chimeric molecule (named drosotoxin) with high selectivity for channel subtypes, which was achieved by using drosomycin to substitute the structural core of BmKITc, a depressant toxin acting on both insect and mammalian Na+ channels. Recombinant drosotoxin selectively inhibited tetrodotoxin-resistant (TTX-R) Na+ channels in rat dorsal root ganglion (DRG) neurons with a 50% inhibitory concentration (IC50) of 2.6 ± 0.5 μM. This chimeric peptide showed no activity on K+, Ca2+ and TTX-sensitive (TTX-S) Na+ channels in rat DRG neurons and Drosophila para/tipE channels at micromolar concentrations. Drosotoxin represents the first chimeric toxin and example of a non-toxic core scaffold with high selectivity on mammalian TTX-R Na+ channels. 相似文献
9.
We have studied the interaction between the SK2 channel and different scorpion toxins in order to find similarity and differences to other K+ channels. Beside apamin, ScTX is a high affinity blocker of the SK2 channel, whereas CTX is unable to block current through SK2. In order to prove that the ScTX affinity can be explained by the character of the different residues in the outer pore of the SK channels we introduced point mutations that render SK2 K+ channel SK1 and SK3 like. Directed by the results of the toxin receptor on the ShakerK+ channel, we changed single amino acids of the SK2 K+ channel that should render it sensitive to other peptide toxins like CTX a blocker of the IK channel, or KTX a blocker of the voltage-dependent channel Kv1.1 and Kv1.3. Amino acids V342G, S344E, and G384D of SK2 were changed to amino acids known from ShakerK+ channel to improve Shaker K+ channel CTX sensitivity. Interestingly SK2 V342G became CTX sensitive with a Kd of 19 nM and was also KTX sensitive Kd=97 nM. SK2 S344E (KdCTX=105 nM,KdKTX=144 nM) and G348D (KdCTX=31 nM,Kd KTX=89 nM) became also CTX and KTX sensitive with a lower affinity. The mutant channels SK V342G, SK2 S344E and SK2 G348D showed reduced ScTX sensitivity (Kd=6 nM,Kd=48 nM, and Kd=12 nM). Because the exchange of a single residue could create a new high affinity binding site for CTX and KTX we concluded that the outer vestibule around position V342, S344, and G348 of the SK2 K+ channel pore is very similar to those of voltage-gated K+ channels such as the Shaker K+ channel, Kv1.1 and Kv1.3 channels and also to the prokaryotic KcsA channel. From mutant cycle analysis of KTX position H34 and SK2 position V342G, S344E, and G348D we could deduce that KTX binds in a similar way to SK2 channel mutant pore than to the Kv1.1 pore. 相似文献
10.
Electrophysiological investigations have previously suggested that phospholipase A2 (PLA2) neurotoxins from snake venoms increase the release of acetylcholine (Ach) at the neuromuscular junction by blocking voltage-gated K+ channels in motor nerve terminals.We have tested some of the most potent presynaptically-acting neurotoxins from snake venoms, namely β-bungarotoxin (BuTx), taipoxin, notexin, crotoxin, ammodytoxin C and A (Amotx C & A), for effects on several types of cloned voltage-gated K+ channels (mKv1.1, rKv1.2, mKv1.3, hKv1.5 and mKv3.1) stably expressed in mammalian cell lines. By use of the whole-cell configuration of the patch clamp recording technique and concentrations of toxins greater than those required to affect acetylcholine release, these neurotoxins have been shown not to block any of these voltage-gated K+ channels. In addition, internal perfusion of the neurotoxins (100 μg/ml) into mouse B82 fibroblast cells that expressed rKv1.2 channels also did not substantially depress K+ currents. The results of this study suggest that the mechanism by which these neurotoxins increase the release of acetylcholine at the neuromuscular junction is not related to the direct blockage of voltage-activated Kv1.1, Kv1.2, Kv1.3, Kv1.5 and Kv3.1 K+ channels. 相似文献
11.
Molecular dynamics (MD) simulations are used to examine the binding modes of two scorpion toxins, margatoxin (MgTx) and hongotoxin (HgTx), to the voltage gated K+ channel, Kv1.3. Using steered MD simulations, we insert either Lys28 or Lys35 of the toxins into the selectivity filter of the channel. The MgTx-Kv1.3 complex is stable when the side chain of Lys35 from the toxin occludes the channel filter, suggesting that Lys35 is the pore-blocking residue for Kv1.3. In this complex, Lys28 of the toxin forms one additional salt bridge with Asp449 just outside the filter of the channel. On the other hand, HgTx forms a stable complex with Kv1.3 when the side chain of Lys28 but not Lys35 protrudes into the filter of the channel. A survey of all the possible favorable binding modes of HgTx-Kv1.3 is carried out by rotating the toxin at 3° intervals around the channel axis while the position of HgTx-Lys28 relative to the filter is maintained. We identify two possible favorable binding modes: HgTx-Arg24 can interact with either Asp433 or Glu420 on the vestibular wall of the channel. The dissociation constants calculated from the two binding modes of HgTx-Kv1.3 differ by approximately 20 fold, suggesting that the two modes are of similar energetics. 相似文献
12.
J Wu W-G Ding H Matsuura K Tsuji W-J Zang M Horie 《British journal of pharmacology》2009,156(2):377-387
Background and purpose:
Kv1.5 channels conduct the ultra-rapid delayed rectifier potassium current (IKur), and in humans, Kv1.5 channels are highly expressed in cardiac atria but are scarce in ventricles. Pharmacological blockade of human Kv1.5 (hKv1.5) has been regarded as effective for prevention and treatment of re-entry-based atrial tachyarrhythmias. Here we examined blockade of hKv1.5 channels by , a well-known inhibitor of phosphatidylinositol 3-kinase (PI3K). LY294002Experimental approach:
hKv1.5 channels were heterologously expressed in Chinese hamster ovary cells. Effects of on wild-type and mutant (T462C, H463C, T480A, R487V, A501V, I502A, I508A, L510A and V516A) hKv1.5 channels were examined by using the whole-cell patch-clamp method. LY294002Key results:
rapidly and reversibly inhibited hKv1.5 current in a concentration-dependent manner (IC50 of 7.9 µmol·L−1). In contrast, wortmannin, a structurally distinct inhibitor of PI3K, had little inhibitory effect on hKv1.5 current. LY294002 block of hKv1.5 current developed with time during depolarizing voltage-clamp steps, and this blockade was also voltage-dependent with a steep increase over the voltage range for channel openings. The apparent binding (k+1) and unbinding (k−1) rate constants were calculated to be 1.6 µmol·L−1−1·s−1 and 5.7 s−1 respectively. Inhibition by LY294002 was significantly reduced in several hKv1.5 mutant channels: T480A, R487V, I502A, I508A, L510A and V516A. LY294002Conclusions and implications:
acts directly on hKv1.5 currents as an open channel blocker, independently of its effects on PI3K activity. Amino acid residues located in the pore region (Thr480, Arg487) and the S6 segment (Ile502, Ile508, Leu510, Val516) appear to constitute potential binding sites for LY294002. LY294002相似文献13.
Ricardo Caballero Eva Delpón Carmen Valenzuela Mónica Longobardo Laura Franqueza Juan Tamargo 《British journal of pharmacology》1997,122(5):796-798
The effects of descarboethoxyloratadine (DCL), the major metabolite of loratadine, were studied on a human cardiac K+ channel (hKv1.5) cloned from human ventricle and stably expressed in a mouse cell line by means of the patch-clamp technique. DCL (1–100 μM) inhibited hKv1.5 current in a concentration-dependent manner with an apparent affinity constant of 12.5±1.2 μM. The blockade increased steeply over the voltage range of channel opening, which indicated that DCL binds preferentially to the open state of the channel. At more depolarized potentials a weaker voltage-dependence was observed consistent with a binding reaction sensing ≈amp;20% of the transmembrane electrical field. DCL, 20 μM, increased the time constant of deactivation of tail currents, thus inducing a ‘crossover'' phenomenon. The present results demonstrated that DCL blocked hKv1.5 channels in a concentration-, voltage-, and time-dependent manner. 相似文献
14.
Núria Villalonga Miren David Joanna Bielańska Antonio Felipe 《Biochemical pharmacology》2010,80(6):858-18
Kv1.3 plays a crucial role in the activation and proliferation of T-lymphocytes and macrophages. While Kv1.3 is responsible for the voltage-dependent potassium current in T-cells, in macrophages this K+ current is generated by the association of Kv1.3 and Kv1.5. Patients with autoimmune diseases show a high number of effector memory T cells that are characterized by a high expression of Kv1.3 and Kv1.3 antagonists ameliorate autoimmune disorders in vivo. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used in patients who suffer from painful autoimmune diseases such as rheumatoid arthritis. In this study, we show that diclofenac impairs immune response via a mechanism that involves Kv1.3. While diclofenac inhibited Kv1.3 expression in activated macrophages and T-lymphocytes, Kv1.5 remained unaffected. Diclofenac also decreased iNOS levels in Raw 264.7 cells, impairing their activation in response to lipopolysaccharide (LPS). LPS-induced macrophage migration and IL-2 production in stimulated Jurkat T-cells were also blocked by pharmacological doses of diclofenac. These effects were mimicked by Margatoxin, a specific Kv1.3 inhibitor, and Charybdotoxin, which blocks both Kv1.3 and Ca2+-activated K+ channels (KCa3.1). Because Kv1.3 is a very good target for autoimmune therapies, the effects of diclofenac on Kv1.3 are of high pharmacological relevance. 相似文献
15.
BACKGROUND AND PURPOSE
Kv11.1 channels are involved in regulating cellular excitability in various tissues including brain, heart and smooth muscle. In these tissues, at least two isoforms, Kv11.1a and Kv11.1b, with different kinetics, are expressed. Kv11.1 activators are potential therapeutic agents, but their effects have only been tested on the Kv11.1a isoform. In this study, the effects of two different Kv11.1 activators, NS1643 and RPR260243, were characterized on Kv11.1a and Kv11.1b channels.EXPERIMENTAL APPROACH
Kv11.1a and Kv11.1b channels were expressed in Xenopus laevis oocytes, and currents were measured using two-electrode voltage clamp. I/V curves and channel kinetics were measured before and after application of 30 µM NS1643 or 10 µM RPR260243.KEY RESULTS
NS1643 increased steady-state currents through Kv11.1b several fold more than through Kv11.1a channels, without affecting EC50 values. NS1643 increased activation rates and decreased rates of inactivation, recovery from inactivation and deactivation for both channels. Except for activation, where effect of NS1643 was comparable, relative changes were greater for Kv11.1b than for Kv11.1a. RPR260243 increased steady-state currents only through Kv11.1a channels, but slowed the process of deactivation for both channels primarily by decreasing time constant of slow deactivation. This effect was greater on Kv11.1b than on Kv11.1a. Effects of both compounds on heteromeric Kv11.1a/Kv11.1b channels were similar to those on Kv11.1a.CONCLUSIONS AND IMPLICATIONS
Both NS1643 and RPR260243 displayed differential effects on Kv11.1a and Kv11.1b channels, the effects being relatively more pronounced on Kv11.1b channels. This affirms the importance of testing the effect of Kv11.1 activators on different channel isoforms. 相似文献16.
Budni J Freitas AE Binfaré RW Rodrigues AL 《Pharmacology, biochemistry, and behavior》2012,101(1):148-154
Potassium (K+) channels have been implicated in depressive disorders and in the mechanism of action of antidepressants. Considering that several studies have indicated that folic acid plays an important role in the pathophysiology of depression, the present study investigated the involvement of potassium channels in the antidepressant-like effect of this vitamin. For this aim, the effect of the combined administration of different types of K+ channel blockers and folic acid in the forced swimming test (FST) was investigated. Treatment of mice by intracerebroventricular (i.c.v.) route with subactive doses of glibenclamide (an ATP-sensitive K+ channels blocker, 0.5 pg/site), charybdotoxin (a large- and intermediate-conductance calcium-activated K+ channel blocker, 25 pg/site) or apamin (a small-conductance calcium-activated K+ channel blocker, 10 pg/site), augmented the effect of folic acid (10 mg/kg, p.o., subeffective dose) in the FST. Additionally, the administration of folic acid and the K+ channel blockers, alone or in combination, did not affect locomotion in the open-field test. Moreover, the reduction in the immobility time in the FST elicited by folic acid administered at a higher dose (50 mg/kg, p.o.) was prevented by the pretreatment of mice with the K+ channel opener cromakalim (10 μg/site, i.c.v.), without affecting locomotor activity. The results of this study indicate that the antidepressant-like effect of folic acid in the FST may be at least partly due to its modulatory effects on neuronal excitability, via inhibition of K+ channels. 相似文献
17.
Asthma affects 10% of the UK population and is an important cause of morbidity and mortality at all ages. Current treatments are either ineffective or carry unacceptable side effects for a number of patients; in consequence, development of new approaches to therapy are important. Ion channels are emerging as attractive therapeutic targets in a variety of non-excitable cells. Ion channels conducting K+ modulate the activity of several structural and inflammatory cells which play important roles in the pathophysiology of asthma. Two channels of particular interest are the voltage-gated K+ channel Kv1.3 and the intermediate conductance Ca2+-activated K+ channel KCa3.1 (also known as IKCa1 or SK4). Kv1.3 is expressed in IFNγ-producing T cells while KCa3.1 is expressed in T cells, mast cells, macrophages, airway smooth muscle cells, fibroblasts and epithelial cells. Both channels play important roles in cell activation, migration, and proliferation through the regulation of membrane potential and calcium signalling. We hypothesize that KCa3.1- and/or Kv1.3-dependent cell processes are one of the common denominators in asthma pathophysiology. If true, these channels might serve as novel targets for the treatment of asthma. Emerging evidence lends support to this hypothesis. Further validation through the study of the role that these channels play in normal and asthmatic airway cell (patho)physiology and in vivo models will provide further justification for the assessment of small molecule blockers of Kv1.3 and KCa3.1 in the treatment of asthma. 相似文献
18.
Rebecca A Roof David L Roman Samuel T Clements Katarzyna Sobczyk-Kojiro Levi L Blazer Shodai Ota Henry I Mosberg Richard R Neubig 《BMC pharmacology》2009,9(1):1-11
Background
K+ and Na+ channel toxins constitute a large set of polypeptides, which interact with their ion channel targets. These polypeptides are classified in two different structural groups. Recently a new structural group called birtoxin-like appeared to contain both types of toxins has been described. We hypothesized that peptides of this group may contain two conserved structural motifs in K+ and/or Na+ channels scorpion toxins, allowing these birtoxin-like peptides to be active on K+ and/or Na+ channels.Results
Four multilevel motifs, overrepresented and specific to each group of K+ and/or Na+ ion channel toxins have been identified, using GIBBS and MEME and based on a training dataset of 79 sequences judged as representative of K+ and Na+ toxins. Unexpectedly birtoxin-like peptides appeared to present a new structural motif distinct from those present in K+ and Na+ channels Toxins. This result, supported by previous experimental data, suggests that birtoxin-like peptides may exert their activity on different sites than those targeted by classic K+ or Na+ toxins. Searching, the nr database with these newly identified motifs using MAST, retrieved several sequences (116 with e-value < 1) from various scorpion species (test dataset). The filtering process left 30 new and highly likely ion channel effectors. Phylogenetic analysis was used to classify the newly found sequences. Alternatively, classification tree analysis, using CART algorithm adjusted with the training dataset, using the motifs and their 2D structure as explanatory variables, provided a model for prediction of the activity of the new sequences.Conclusion
The phylogenetic results were in perfect agreement with those obtained by the CART algorithm. Our results may be used as criteria for a new classification of scorpion toxins based on functional motifs. 相似文献19.
Liu Y Xu XH Liu Z Du XL Chen KH Xin X Jin ZD Shen JZ Hu Y Li GR Jin MW 《Biochemical pharmacology》2012,84(4):498-506
The natural flavones and polymethylflavone have been reported to have cardiovascular protective effects. In the present study, we determined whether quecertin, apigenin and their methylated compounds (3,7,3′,4′-tetramethylquecertin, 3,5,7,3′,4′-pentamethylquecertin, 7,4′-dimethylapigenin, and 5,7,4′-trimethylapigenin) would block the atrial specific potassium channel hKv1.5 using a whole-cell patch voltage-clamp technique. We found that only trimethylapigenin showed a strong inhibitory effect on hKv1.5 channel current. This compound suppressed hKv1.5 current in HEK 293 cell line (IC50 = 6.4 μM), and the ultra-rapid delayed rectify K+ current IKur in human atrial myocytes (IC50 = 8.0 μM) by binding to the open channels and showed a use- and frequency-dependent manner. In addition, trimethylapigenin decreased transient outward potassium current (Ito) in human atrial myocytes, inhibited acetylcholine-activated K+ current (IC50 = 6.8 μM) in rat atrial myocytes. Interestingly, trimethylapigenin had a weak inhibition of hERG channel current. Our results indicate that trimethyapigenin significantly inhibits the atrial potassium currents hKv1.5/IKur and IKACh, which suggests that trimethylapigenin may be a potential candidate for anti-atrial fibrillation. 相似文献
20.
Seojin Park Minji Kang Ryeon Heo Seo-Yeong Mun Minju Park Eun-Taek Han Jin-Hee Han Wanjoo Chun Hongzoo Park Won Sun Park 《The Korean journal of physiology & pharmacology》2022,26(5):397
Fesoterodine, an antimuscarinic drug, is widely used to treat overactive bladder syndrome. However, there is little information about its effects on vascular K+ channels. In this study, voltage-dependent K+ (Kv) channel inhibition by fesoterodine was investigated using the patch-clamp technique in rabbit coronary artery. In whole-cell patches, the addition of fesoterodine to the bath inhibited the Kv currents in a concentration-dependent manner, with an IC50 value of 3.19 ± 0.91 μM and a Hill coefficient of 0.56 ± 0.03. Although the drug did not alter the voltage-dependence of steady-state activation, it shifted the steady-state inactivation curve to a more negative potential, suggesting that fesoterodine affects the voltage-sensor of the Kv channel. Inhibition by fesoterodine was significantly enhanced by repetitive train pulses (1 or 2 Hz). Furthermore, it significantly increased the recovery time constant from inactivation, suggesting that the Kv channel inhibition by fesoterodine is use (state)-dependent. Its inhibitory effect disappeared by pretreatment with a Kv 1.5 inhibitor. However, pretreatment with Kv2.1 or Kv7 inhibitors did not affect the inhibitory effects on Kv channels. Based on these results, we conclude that fesoterodine inhibits vascular Kv channels (mainly the Kv1.5 subtype) in a concentration- and use (state)-dependent manner, independent of muscarinic receptor antagonism. 相似文献