AA sequence: Gly-Val-Glu-Ile-Asn-Val-Lys-Cys8-Ser-Gly-Ser-Pro-Gln-Cys14-Leu-Lys-Pro-Cys18-Lys-Asp-Ala-Gly-Met-Arg-Phe-Gly-Lys-Cys28-Met-Asn-Arg-Lys-Cys33-His-Cys35-Thr-Pro-Lys-OH
(Disulfide bonds between Cys8-Cys28, Cys14-Cys33 and Cys18-Cys35)
Length (aa): 38
Formula: C171H283N55O49S6
Molecular Weight: 4149.89 Da
Appearance: White lyophilized solid
Solubility: water and saline buffer
CAS number:
Source: Synthetic
Purity rate: > 97 %
Kaliotoxin-1
Potent blocker of potassium channels
Kaliotoxin-1 (KTX1) has been isolated from the venom of the Scorpion Androctonus mauretanicus mauretanicus. Kaliotoxin-1 shows a high structural affinity with Iberiotoxin and Charybdotoxin that inhibit KCa2+ channels activity. According to several studies, it appears that Kaliotoxin-1 has a weak inhibitory effect on KCa2+ channels, but it is a potent and selective inhibitor of voltage-activated potassium channel (Kv1.1, Kv1.2, Kv1.3).
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Neuropathophysiological effect and immuno-inflammatory response induced by kaliotoxin of androctonus scorpion venom
Kaliotoxin (KTX) is a neurotoxin purified from Androctonus scorpion venom. Purification and pharmacological and immunological characterization of this neurotoxin has been extensively studied, but its biological effects have not. The ability of KTX to induce neuropathophysiological and immuno-inflammatory effects was investigated. NMRI mice were injected with a sublethal dose of KTX (20 ng/20 g of body weight) or saline solution via the intra-cerebro-ventricular route. Tissue damage and immunological biomarkers such as eosinophil peroxidase (EPO), myeloperoxidase (MPO), and nitric oxide (NO) were analyzed in serum, brain, lung, and heart tissue. Protein levels, LDH, and CPK activities were also determined in serum 24 h after injection. In this study, KTX injection induced severe alterations in the cerebral cortex, myocardium, and pulmonary parenchyma. Tissue damage was correlated with seric increase in creatine kinase and lactate dehydrogenase activities. KTX also induced an immuno-inflammatory response distinguished by cell infiltration characterized by a significant increase in EPO and MPO activities in the brain, heart, and lungs. This infiltration was also associated with an increase in albumin, α-, β-, and γ-globulin fractions, and NO release. KTX binding to its targets in CNS (Kv1.1 and Kv1.3 channels) may induce severe modifications in the structure and function of various organs associated with the activation of immuno-inflammatory reactions.
Heterogeneous competition of Kv1 channel toxins with kaliotoxin for binding in rat brain: autoradiographic analysis
Kaliotoxin, a Kv1.1 and Kv1.3 channel blocker, improves associative learning in rats
Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation
Distribution in rat brain of binding sites of kaliotoxin, a blocker of Kv1.1 and Kv1.3 alpha-subunits
3D structure of kaliotoxin: is residue 34 a key for channel selectivity?
T cell activation is regulated by voltage-dependent and calcium-activated potassium channels
Membrane potential (Vm) is tightly controlled in T cells through the regulated flux of ions across the plasma membrane. To investigate the functional role of voltage-dependent (Kv) and calcium-activated (KCa) potassium channels in T cell activation, we compared the effects of two K+ channel blockers, namely kaliotoxin (KTX) and charybdotoxin (CHTX), on Vm, calcium influx, and cell proliferation. KTX potently inhibited Kv (ID50 = 3 nM) but not KCa (ID50 = 5 microM) currents in T cells. Resting T cells exposed to KTX (300 nM) depolarized from -56 mV to -50 mV. KTX had no effect on the transient membrane hyperpolarization that characteristically follows receptor-mediated T cell stimulation. However, T cells stimulated in the presence of KTX subsequently depolarized to -40 mV. KTX also reduced the steady state intracellular free calcium concentration ([Ca2+]i) in stimulated cells by 19% and inhibited T cell proliferation by 35%. CHTX potently inhibited both Kv and KCa currents (ID50 = approximately 1 nM). CHTX (300 nM) depolarized resting T cells to -48 mV, equivalent to the effect observed for KTX. In stimulated T cells, 300 nM CHTX completely blocked the induced hyperpolarization and subsequently depolarized the cells to -21 mV. These effects were associated with a 45% reduction in peak [Ca2+]i, a 60% decrease in steady state [Ca2+]i, and 63% inhibition of T cell proliferation. These results suggest that both Kv and KCa conductances contribute to the underlying mechanisms of T cell activation.
Rader RK, et al. (1997) T cell activation is regulated by voltage-dependent and calcium-activated potassium channels. J Immunol. PMID: 8568243
Effects of channel modulators on cloned large-conductance calcium-activated potassium channels
Through expression of the cloned mouse (mSlo) or human (hSlo) large-conductance (BK) Ca(2+)-activated K+ channel in Xenopus laevis oocytes and HEK 293 cells, we characterized the effects of reported blockers and openers of BK channels to initiate the study of the molecular determinants of BK channel modulation. In oocytes, iberiotoxin and charybdotoxin, peptidyl scorpion toxins, were both equally effective blockers of BK current, although iberiotoxin was significantly more potent than charybdotoxin. The structurally related peptide kaliotoxin was not a potent blocker of BK current. Paxilline, a fungal tremorgenic alkaloid, was an effective but complex blocker of BK current. Tetrandrine, a putative blocker of type II BK channels, and ketamine were relatively ineffective. The putative BK openers NS004 and NS1619, phloretin, niflumic acid, flufenamic acid, and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) increased BK current in oocytes at microM concentrations; many of these produced biphasic concentration-response relationships. Coapplication of representative blockers and openers revealed several patterns of interaction, including competitive and noncompetitive antagonism. NS1619, niflumic acid, and phloretin were tested by using excised inside-out membrane patches from HEK 293 cells and were found to increase the activity of hSlo BK channels and produce a leftward shift in the G/Gmax-versus-voltage relationship of these channels. These results represent the first comprehensive examination of the molecular pharmacology of BK channels.
Gribkoff VK. 1996) Effects of channel modulators on cloned large-conductance calcium-activated potassium channels. Mol Pharmacol. PMID: 8700114
Pharmacological properties of Ca2+activated K+ currents of ramified murine brain macrophages
Using the whole-cell configuration of the patch clamp technique, calcium-activated potassium currents (I(K,Ca)) were investigated in ramified murine brain macrophages. In order to induce I(K,Ca) the intracellular concentration of nominal free Ca2+ was adjusted to 1 microM. The Ca2+-activated K+ current of brain macrophages did not show any voltage dependence at test potentials between -120 and +30 mV. A tenfold change in extracellular K+ concentration shifted the reversal potential of I(K,Ca) by 51 mV. The bee venom toxin apamin applied at concentrations of up to 1 microM did not affect I(K,Ca). Ca2+-activated K+ currents of ramified brain macrophages were highly sensitive to extracellularly applied charybdotoxin (CTX). The half-maximal effective concentration of CTX was calculated to be 4.3 nM. In contrast to CTX, the scorpion toxin kaliotoxin did not inhibit I(K,Ca) at concentrations between 1 and 50 nM. Tetraethylammonium (TEA) blocked 8.0% of I(K,Ca) at a concentration of 1 mM, whereas 31.4% of current was blocked by 10 mM TEA. Several inorganic polyvalent cations were tested at a concentration of 2 mM for their ability to block I(K,Ca). La3+ reduced I(K,Ca) by 72.8%, whereas Cd2+ decreased I(K,Ca) by 17.4%; in contrast, Ni2+ did not have any effect on I(K,Ca). Ba2+ applied at a concentration of 1 mM reduced I(K,Ca) voltage-dependently at hyperpolarizing potentials.
Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom
A peptidyl inhibitor of the high conductance Ca(2+)-activated K+ channels (KCa) has been purified to homogeneity from the venom of the scorpion Androctonus mauretanicus mauretanicus. The peptide has been named kaliotoxin (KTX). It is a single 4-kDa polypeptide chain. Its complete amino acid sequence has been determined. KTX displays sequence homology with other scorpion-derived inhibitors of Ca(2+)-activated or voltage-gated K+ channels: 44% homology with charybdotoxin (CTX), 52% with noxiustoxin (NTX), and 44% with iberiotoxin (IbTX). Electrophysiological experiments performed in identified nerve cells from the mollusc Helix pomatia showed that KTX specifically suppressed the whole cell Ca(2+)-activated K+ current. KTX had no detectable effects on voltage-gated K+ current (delayed rectifier and fast transient A current) or on L-type Ca2+ currents. KTX interacts in a one-to-one way with KCa channels with a Kd of 20 nM. Single channel experiments were performed on high conductance KCa channels excised from the above Helix neurons and from rabbit coeliac ganglia sympathetic neurons. KTX acted exclusively at the outer face of the channel. KTX applied on excised outside-out KCa channels induced a transient period of fast-flicker block followed by a persistent channel blockade. The KTX-induced block was not voltage-dependent which suggests differences in the blockade of KCa channels by KTX and by CTX. Comparison of KTX and CTX sequences leads to the identification of a short amino acid sequence (26-33) which may be implicated in the toxin-channel interaction. KTX therefore appears to be a useful tool for elucidating the molecular pharmacology of the high conductance Ca(2+)-activated K+ channel.
Crest M., et al. (1992) Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom. JBC. PMID: 1730708