AA sequence: Gly-Val-Asp-Lys-Ala-Gly-Cys7-Arg-Tyr-Met-Phe-Gly-Gly-Cys14-Ser-Val-Asn-Asp-Asp-Cys20-Cys21-Pro-Arg-Leu-Gly-Cys26-His-Ser-Leu-Phe-Ser-Tyr-Cys33-Ala-Trp-Asp-Leu-Thr-Phe-Ser-Asp-OH
Disulfide bonds: Cys7-Cys21, Cys14-Cys26 and Cys20-Cys33
Length (aa): 41
Formula: C192H274N52O60S7
Molecular Weight: 4496.42 Da
Appearance: White lyophilized solid
Solubility: water and saline buffer
CAS number: 203460-30-4
Source: Synthetic
Purity rate: > 95 %
SNX482
Selective blocker of Cav2.3 channel
SNX-482 has been isolated from the venom of the Spider Hysterocrates gigas (African tarantula). SNX-482 modulates the R-type current associated with the class α1E calcium channel (Cav2.3 from the CACNA1E gene). SNX-482 antagonizes channel activation by inducing a depolarizing shift in the activation potential, thus preventing the channel from undergoing normal membrane depolarization. SNX-482 acts rapidly and maintains its effect.
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The Cav2.3 calcium channel antagonist SNX-482 reduces dorsal horn neuronal responses in a rat model of chronic neuropathic pain
Neuropathic pain is a difficult state to treat, characterized by alterations in sensory processing that can include allodynia (touch-evoked pain). Evidence exists for nerve damage-induced plasticity in both transmission & modulatory systems, including changes in voltage-dependent calcium channel (VDCC) expression & function; however, the role of Ca(v)2.3 calcium channels has not clearly been defined. Here, the effects of SNX-482, a selective Ca(v)2.3 antagonist, on sensory transmission at the spinal cord level have been investigated in the rat. The spinal nerve ligation (SNL) model of chronic neuropathic pain [Kim & Chung, (1992)Pain, 50, 355-363] was used to induce mechanical allodynia, as tested on the ipsilateral hindpaw. In vivo electrophysiological measurements of dorsal horn neuronal responses to innocuous & noxious electrical and natural stimuli were made after SNL & compared to sham-operated animals. Spinal SNX-482 (0.5-4 microg/50 microL) exerted dose-related inhibitions of noxious C-fibre- and Adelta-fibre-mediated neuronal responses in conditions of neuropathy, but not in sham-operated animals. Measures of spinal cord hyperexcitability & nociception were most susceptible to SNX-482. In contrast, non-noxious Abeta-mediated responses were not affected by SNX-482. Moreover, responses to innocuous mechanical & also thermal stimuli were more sensitive to SNX-482 in SNL than control animals. This study is the first to demonstrate an antinociceptive role for SNX-482-sensitive channels in dorsal horn neurons during neuropathy. These data are consistent with plasticity in Ca(V)2.3 calcium channel expression and suggest a potential selective target to reduce nociceptive transmission during conditions of nerve damage.
Matthews EA., et al. (2007) The Cav2.3 calcium channel antagonist SNX-482 reduces dorsal horn neuronal responses in a rat model of chronic neuropathic pain. Eur J Neurosci. PMID 17610575
SNX482 selectively blocks P/Q Ca2+ channels and delays the inactivation of Na+ channels of chromaffin cells
The effects of the toxin SXN482 on Ca2+ channel currents (ICa), Na+ currents (INa), and K+ currents (IK) have been studied in bovine adrenal medullary chromaffin cells voltage-clamped at -80 mV. Currents were elicited by depolarising pulses to 0-10 mV (ICa and INa) or to +60 mV (IK). SNX482 blocked ICa in a concentration-dependent manner. The inhibition curve exhibited two phases. The first high-affinity phase comprised 28% of the whole-cell current & exhibited an IC50 of 30.2 nM. The second low-affinity phase comprised over 70% of ICa & had an IC50 of 758.6 nM. Blockade was rapid and fully reversible upon washout of the toxin. Occlusion experiments showed additivity of blockade exerted by nifedipine plus SNX482 (0.3 microM) and by omega-conotoxin GVIA plus SNX482. In contrast, blockade exerted by combined omega-agatoxin IVA plus SNX482 (about 50% of the whole cell) did not show additivity. At 0.3 microM and higher concentrations, SNX482 delayed the inactivation of INa. The time constant (tau) for inactivation of INa in control conditions doubled in the presence of 0.5 microM SNX482. At 0.3 microM, SNX482 did not affect IK. Our data demonstrate that: (i) SNX482 selectively blocks P/Q Ca2+ channels at submicromolar concentrations; (ii) the toxin partially blocks Na+ channels; (iii) SNX482 delays the inactivation of Na+ channels. These results reveal novel properties of SNX482 and cast doubts on the claimed selectivity & specificity of the toxin to block the R-type Ca2+ channel.
Arroyo G, et al. (2003) SNX482 selectively blocks P/Q Ca2+ channels and delays the inactivation of Na+ channels of chromaffin cells, Eur J Pharmacol. PMID: 12954354
Interaction of SNX482 with domains III and IV inhibits activation gating of alpha(1E) (Ca(V)2.3) calcium channels
Bourinet, E., et al. (2001) Interaction of SNX482 with domains III and IV inhibits activation gating of alpha(1E) (Ca(V)2.3) calcium channels, Biophys. PMID 11423396
Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas
We describe the first potent and selective blocker of the class E Ca2+channel. SNX-482, a novel 41 amino acid peptide present in the venom of the African tarantula, Hysterocrates gigas, was identified through its ability to inhibit human class E Ca2+ channels stably expressed in a mammalian cell line. An IC50 of 15-30 nM was obtained for block of the class E Ca2+ channel, using either patch clamp electrophysiology or K+-evoked Ca2+ flux. At low nanomolar concentrations, SNX-482 also blocked a native resistant or R-type Ca2+ current in rat neurohypophyseal nerve terminals, but concentrations of 200-500 nM had no effect on R-type Ca2+ currents in several types of rat central neurons. The peptide has the sequence GVDKAGCRYMFGGCSVNDDCCPRLGCHSLFSYCAWDLTFSD-OH and is homologous to the spider peptides grammatoxin S1A and hanatoxin, both peptides with very different ion channel blocking selectivities. No effect of SNX-482 was observed on the following ion channel activities: Na+ or K+ currents in several cultured cell types (up to 500 nM); K+ current through cloned potassium channels Kv1.1 and Kv1. 4 expressed in Xenopus oocytes (up to 140 nM); Ca2+ flux through L- and T-type Ca2+ channels in an anterior pituitary cell line (GH3, up to 500 nM); and Ba2+ current through class A Ca2+ channels expressed in Xenopus oocytes (up to 280 nM). A weak effect was noted on Ca2+ current through cloned and stably expressed class B Ca2+ channels (IC50 > 500 nM). The unique selectivity of SNX-482 suggests its usefulness in studying the diversity, function, and pharmacology of class E and/or R-type Ca2+ channels.
Newcomb, R., et al. (1998) Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas, Biochemistry. PMID: 9799496