Molecular basis of α-KTx specificity

Giangiacomo, Kathleen M.; Ceralde, Yamille; Mullmann, Theodore J.

doi:10.1016/j.toxicon.2003.11.029

Cited by 44 publications

(44 citation statements)

References 46 publications

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“…The selectivity of Vm24 for Kv1.3 over other ion channels tested is at least 1500-fold, on the basis of the K d value obtained from the dose-response relationship and the single-concentration estimates of the K d values for the channels that were inhibited by Vm24. This value is well over the commonly accepted criterion for selectivity, which is defined as a 100-fold difference in the equilibrium dissociation constants for ␣-KTx binding to two different potassium channels (Giangiacomo et al, 2004). The ion channels that were inhibited with 10 nM Vm24 were Kv1.1, Kv1.2, and KCa3.1, whereas other tested channels were practically resistant to Vm24.…”

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confidence: 66%

Vm24, a Natural Immunosuppressive Peptide, Potently and Selectively Blocks Kv1.3 Potassium Channels of Human T Cells

et al. 2012

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Blockade of Kv1.3 K ϩ channels in T cells is a promising therapeutic approach for the treatment of autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus. Vm24 (␣-KTx 23.1) is a novel 36-residue Kv1.3-specific peptide isolated from the venom of the scorpion Vaejovis mexicanus smithi. Vm24 inhibits Kv1.3 channels of human lymphocytes with high affinity (K d ϭ 2.9 pM) and exhibits Ͼ1500-fold selectivity over other ion channels assayed. It inhibits the proliferation and Ca 2ϩ signaling of human T cells in vitro and reduces delayed-type hypersensitivity reactions in rats in vivo. Our results indicate that Vm24 has exceptional pharmacological properties that make it an excellent candidate for treatment of certain autoimmune diseases.

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Section: Downloaded Fromsupporting

confidence: 66%

Vm24, a Natural Immunosuppressive Peptide, Potently and Selectively Blocks Kv1.3 Potassium Channels of Human T Cells

et al. 2012

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“…In contrast, maurotoxin inhibits K v 1.1, K v 1.2, and K v 1.3 channels with a smaller degree of selectivity. Specificity for a given channel requires a minimum a 100-fold difference in IC 50 (Giangiacomo et al, 2004 MD simulation is a powerful tool at the molecular level for understanding the electrophysiologic experiments we performed. The MD simulation shows that residue lysines 16, 17, and 30 and arginine-9 are critical for the blocking of the hK v 1.2 channel, and the residues involved from the channel are the acidic residues aspartate (363 and 379) and glutamate (355 and 353).…”

Section: Discussionmentioning

confidence: 99%

“…These data mean that urotoxin is ∼560-fold selective for hK v 1.2 over hK v 1.3 and ∼1600-fold when compared with hK v 1.1. Based on the classification of Giangiacomo et al (2004), urotoxin is selective for the hK v 1.2 over the hK v 1.1 and hK v 1.3 channels. Due to its unique binding geometry to K 1 channels (see below), whether urotoxin inhibits the toxin-resistant hK v 1.5 channel was also tested.…”

Section: Pharmacologic Effects Of Urotoxinmentioning

confidence: 99%

Structure, Molecular Modeling, and Function of the Novel Potassium Channel Blocker Urotoxin Isolated from the Venom of the Australian Scorpion Urodacus yaschenkoi

et al. 2014

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This communication reports the structural and functional characterization of urotoxin, the first K 1 channel toxin isolated from the venom of the Australian scorpion Urodacus yaschenkoi. It is a basic peptide consisting of 37 amino acids with an amidated C-terminal residue. Urotoxin contains eight cysteines forming four disulfide bridges with sequence similarities resembling the a-potassium channel toxin 6 (a-KTx-6) subfamily of peptides; it was assigned the systematic number of a-KTx-6.21. Urotoxin is a potent blocker of human voltage-gated potassium channel (K v )1.2 channels, with an IC 50 of 160 pM, whereas its affinity for other channels tested was in the nanomolar range (hK v 1

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“…Apamin has long been known as a highly selective inhibitor of Ca 2+ -activated K + channels (16). The cloning of the SK channels (45,56) allowed the molecular analysis of the apaminreceptor interaction, and showed the importance of the pore region (43), a region to which many scorpion and snake toxins bind on voltage-gated K + channels (57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

An Amino Acid Outside the Pore Region Influences Apamin Sensitivity in Small Conductance Ca2+-activated K+ Channels

Nolting

Ferraro

D’hoedt³

et al. 2007

Journal of Biological Chemistry

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Small conductance calcium-activated potassium channels (SK, K Ca ) are a family of voltageindependent K + channels with a distinct physiology and pharmacology. The bee venom toxin apamin inhibits exclusively the three cloned SK channel subtypes (SK1, SK2 and SK3) with different affinity, highest for SK2, lowest for SK1 and intermediate for SK3 channels. The high selectivity of apamin made it a valuable tool to study the molecular makeup and function of native SK channels. Three amino acids located in the outer vestibule of the pore are of particular importance for the different apamin sensitivities of SK channels. Chimeric SK1 channels, enabling the homomeric expression of the rat SK1 (rSK1) subunit and containing the core domain (S1-S6) of rSK1, are apamin insensitive. By contrast, channels formed by the human orthologue hSK1 are sensitive to apamin. This finding hinted to the involvement of regions beyond the pore as determinants of apamin sensitivity, since hSK1 and rSK1 have an identical amino acid sequence in the pore region. Here we investigated which parts of the channels outside the pore region are important for apamin sensitivity by constructing chimeras between apamin insensitive and sensitive SK channel subunits and by introducing point mutations. We demonstrate that a single amino acid situated in the extracellular loop between the transmembrane segments S3 and S4 has a major impact on apamin sensitivity. Our findings enabled us to convert the hSK1 channel into a channel that was as sensitive for apamin as SK2, the SK channel with the highest sensitivity. Ca 2+ -activated K + channels (K Ca ) 1 are activated by rises in intracellular Ca 2+ . The K Ca potassium channel family comprises of at least three subfamilies, K Ca 1-3 (1). Channels containing the K Ca 1.1 α-subunit (BK channels) have large single channel conductance and are maximally activated by micromolar concentrations of intracellular free calcium and concurrent depolarization (2). Their kinetic and pharmacological properties are modified upon assembly with membrane standing ß-subunits (3). The K Ca 2 subfamily of small-conductance Ca 2+ -activated K + channels, also known as SK channels, has three closely related members SK1 (K Ca 2.1), SK2 (K Ca 2.2) and SK3 (K Ca 2.3), which are characterized by a small single channel conductance. The IK channel (K Ca 3.1) shows an intermediate single channel conductance. Both SK and IK channels are voltage independent and activated by submicromolar concentrations of intracellular free Ca 2+ . The gating of SK and IK channels is induced upon Ca 2+ binding to calmodulin, which is constitutively bound to each channel subunit. Ca 2+ * This work was supported by a Wellcome Prize studentship (T.F.) and a Wellcome Trust Senior Research fellowship (M.S.).Address correspondence to: Martin Stocker, Laboratory of Molecular Pharmacology, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK, UKPMC Funders Group Author Manuscript UKPMC Funders Group Author Manuscriptbindin...

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Molecular basis of α-KTx specificity

Cited by 44 publications

References 46 publications

Vm24, a Natural Immunosuppressive Peptide, Potently and Selectively Blocks Kv1.3 Potassium Channels of Human T Cells

Vm24, a Natural Immunosuppressive Peptide, Potently and Selectively Blocks Kv1.3 Potassium Channels of Human T Cells

Structure, Molecular Modeling, and Function of the Novel Potassium Channel Blocker Urotoxin Isolated from the Venom of the Australian Scorpion Urodacus yaschenkoi

An Amino Acid Outside the Pore Region Influences Apamin Sensitivity in Small Conductance Ca2+-activated K+ Channels

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