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Differential molecular information of maurotoxin peptide recognizing IK(Ca) and Kv1.2 channels explored by computational simulation.

ABSTRACT: BACKGROUND: Scorpion toxins are invaluable tools for ion channel research and are potential drugs for human channelopathies. However, it is still an open task to determine the molecular basis underlying the diverse interactions between toxin peptides and ion channels. The inhibitory peptide Maurotoxin (MTX) recognized the distantly related IK(Ca) and Kv1.2 channel with approximately the same potency and using the same functional residues, their differential binding mechanism remain elusive. In this study, we applied computational methods to explore the differential binding modes of MTX to Kv1.2 and IK(Ca) channels, which would help to understand the diversity of channel-toxin interactions and accelerate the toxin-based drug design. RESULTS: A reasonably stable MTX-IK(Ca) complex was obtained by combining various computational methods and by in-depth comparison with the previous model of the MTX-Kv1.2 complex. Similarly, MTX adopted the ?-sheet structure as the interacting surface for binding both channels, with Lys23 occluding the pore. In contrast, the other critical residues Lys27, Lys30, and Tyr32 of MTX adopted distinct interactions when associating with the IK(Ca) channel. In addition, the residues Gln229, Ala230, Ala233, and Thr234 on the IK(Ca) channel turret formed polar and non-polar interactions with MTX, whereas the turret of Kv1.2 was almost not involved in recognizing MTX. In all, the pairs of interacting residues on MTX and the IK(Ca) channel of the bound complex indicated that electrostatic and Van der Waal interactions contributed equally to the formation of a stable MTX-IK(Ca) complex, in contrast to the MTX-Kv1.2 binding that is dominantly mediated by electrostatic forces. CONCLUSIONS: Despite sharing similar pharmacological profiles toward both IK(Ca) and Kv1.2 channels, MTX adopted totally diverging modes in the two association processes. All the molecular information unveiled here could not only offer a better understanding about the structural differences between the IK(Ca) and Kv1.2 channels, but also provide novel structural clues that will help in the designing of more selective molecular probes to discriminate between these two channels.

SUBMITTER: Yi H

PROVIDER: S-EPMC3041654 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Differential molecular information of maurotoxin peptide recognizing IK(Ca) and Kv1.2 channels explored by computational simulation.

Yi Hong H Qiu Su S Wu Yingliang Y Li Wenxin W Wang Baoshan B

BMC structural biology 20110125

<h4>Background</h4>Scorpion toxins are invaluable tools for ion channel research and are potential drugs for human channelopathies. However, it is still an open task to determine the molecular basis underlying the diverse interactions between toxin peptides and ion channels. The inhibitory peptide Maurotoxin (MTX) recognized the distantly related IK(Ca) and Kv1.2 channel with approximately the same potency and using the same functional residues, their differential binding mechanism remain elusiv ...[more]

PMID: 21262000

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Project description:1. Nine bis-quinolinyl and bis-quinolinium compounds related to dequalinium, and previously shown to block apamin-sensitive small conductance Ca(2+)-activated K(+) channels (SK(Ca)), have been tested for their inhibitory effects on actions mediated by intermediate conductance Ca(2+)-activated K(+) channels (IK(Ca)) in rabbit blood cells. 2. In most experiments, a K(+)-sensitive electrode was employed to monitor the IK(Ca)-mediated net loss of cell K(+) that followed the addition of the Ca(2+) ionophore A23187 (2 microM) to red cells suspended at an haematocrit of 1% in a low K(+) (0.12 - 0.17 mM) solution. The remainder used an optical method based on measuring the reduction in light transmission that occurred on applying A23187 (0.4 or 2 microM) to a very dilute suspension of red cells (haematocrit 0.02%). 3. Of the compounds tested, the most potent IK(Ca) blocker was 1,12 bis[(2-methylquinolin-4-yl)amino]dodecane (UCL 1407) which had an IC(50) of 0.85+/-0.06 microM (mean+/-s.d. mean). 4. The inhibitory action of UCL 1407 and its three most active congeners was characterized by (i) a Hill slope greater than unity, (ii) sensitivity to an increase in external [K(+)], and (iii) a time course of onset that suggested use-dependence. Also, the potency of the nonquaternary compounds tested increased with their predicted lipophilicity. These findings suggested that the IK(Ca) blocking action resembles that of cetiedil rather than of clotrimazole. 5. Some quaternized members of the series were also active. The most potent was the monoquaternary UCL 1440 ((1-[N-[1-(3, 5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino]-10-[N'-(2-me thylqu inolinium-4yl)amino] decane (trifluoroacetate) which had an IC(50) of 1.8+/-0.1 microM. The corresponding bisquaternary UCL 1438 (1, 10-bis[N-[1-(3,5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino] decane bis(trifluoroacetate) was almost as active (IC(50) 2.7+/-0.3 microM). 6. A bis-aminoquinolium cyclophane (UCL 1684) had little IK(Ca) blocking action despite its great potency at SK(Ca) channels (IC(50) 4.1+/-0.2 nM). 7. The main outcome is the identification of new intermediate-conductance Ca(2+)-activated K(+) channel blockers with a wide range of IK(Ca)/SK(Ca) selectivities.

Project description:Key pointsEndothelial cell TRPV4 (TRPV4EC ) channels exert a dilatory effect on the resting diameter of resistance mesenteric and pulmonary arteries. Functional intermediate- and small-conductance K+ (IK and SK) channels and endothelial nitric oxide synthase (eNOS) are present in the endothelium of mesenteric and pulmonary arteries. TRPV4EC sparklets preferentially couple with IK/SK channels in mesenteric arteries and with eNOS in pulmonary arteries. TRPV4EC channels co-localize with IK/SK channels in mesenteric arteries but not in pulmonary arteries, which may explain TRPV4EC -IK/SK channel coupling in mesenteric arteries and its absence in pulmonary arteries. The presence of the nitric oxide-scavenging protein, haemoglobin α, limits TRPV4EC -eNOS signalling in mesenteric arteries. Spatial proximity of TRPV4EC channels with eNOS and the absence of haemoglobin α favour TRPV4EC -eNOS signalling in pulmonary arteries.AbstractSpatially localized Ca2+ signals activate Ca2+ -sensitive intermediate- and small-conductance K+ (IK and SK) channels in some vascular beds and endothelial nitric oxide synthase (eNOS) in others. The present study aimed to uncover the signalling organization that determines selective Ca2+ signal to vasodilatory target coupling in the endothelium. Resistance-sized mesenteric arteries (MAs) and pulmonary arteries (PAs) were used as prototypes for arteries with predominantly IK/SK channel- and eNOS-dependent vasodilatation, respectively. Ca2+ influx signals through endothelial transient receptor potential vanilloid 4 (TRPV4EC ) channels played an important role in controlling the baseline diameter of both MAs and PAs. TRPV4EC channel activity was similar in MAs and PAs. However, the TRPV4 channel agonist GSK1016790A (10 nm) selectively activated IK/SK channels in MAs and eNOS in PAs, revealing preferential TRPV4EC -IK/SK channel coupling in MAs and TRPV4EC -eNOS coupling in PAs. IK/SK channels co-localized with TRPV4EC channels at myoendothelial projections (MEPs) in MAs, although they lacked the spatial proximity necessary for their activation by TRPV4EC channels in PAs. Additionally, the presence of the NO scavenging protein haemoglobin α (Hbα) within nanometer proximity to eNOS limits TRPV4EC -eNOS signalling in MAs. By contrast, co-localization of TRPV4EC channels and eNOS at MEPs, and the absence of Hbα, favour TRPV4EC -eNOS coupling in PAs. Thus, our results reveal that differential spatial organization of signalling elements determines TRPV4EC -IK/SK vs. TRPV4EC -eNOS coupling in resistance arteries.

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Differential molecular information of maurotoxin peptide recognizing IK(Ca) and Kv1.2 channels explored by computational simulation.

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Differential molecular information of maurotoxin peptide recognizing IK(Ca) and Kv1.2 channels explored by computational simulation.

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