SNX-482 is a toxin from the tarantula Hysterocrates gigas. It acts as a high-affinity blocker of R-type Ca2+ (Cav2.3) channels, but at higher concentrations it can also block other Ca2+ channels and Na+ channels.

Sources

SNX-482 is isolated from the venom of the spider Hysterocrates gigas.[1]

Sequence

GVDKAGCRYMFGGCSVNDDCCPRLGCHSLFSYCAWDLTFSD-OH[1]

Homology

SNX-482 is homologous to the spider peptides grammatoxin S1A and hanatoxin.[1]

Target

Cav2.3 (alpha1E, R-type) channel (strong affinity), L-type Ca2+ channel, P/Q type Ca2+ channel, Na+ channel.[1][2][3] "SNX-482 [also] dramatically reduced the A-type potassium current in acutely dissociated dopamine neurons from mouse substantia nigra pars compacta."[4]

Mode of action

The compound was initially identified as a selective, voltage-dependent inhibitor of Cav2.3 (a1E, R-type) channels.[1] SNX-482 inhibits native R-type Ca2+ currents at weak nanomolar concentrations in rat neurohypophyseal nerve terminals. However, it does not influence R-type Ca2+ currents at concentrations of 200–500 nM in several types of rat central neurons.[1] Washout could only moderately reverse the R-type Ca2+ channel inhibition after treatment with 200 nM SNX-482. However, application of strong voltage reverses the blocking of R-type Ca2+ channels.[2] SNX-482 needs to interact with a1E domains III and IV to play a role in the significant inhibition of R-type channel gating.[2] Although SNX-482 is generally viewed as a selective inhibitor of Cav2.3 (a1E, R-type) channels, more recently it was shown that it can also inhibit L-type or P/Q type Ca2+ channels and incompletely block Na+ channels.[1][2][3]

Research and therapeutic use

SNX-482 has been used to elucidate the roles of theaflavin-3-G in transmitter release.[5] Furthermore, some research has indicated that it inhibits neuronal responses in a neuropathic pain model, so it is possible that SNX-482 can be used to reduce dorsal horn neuronal pain in neuropathic pain therapy.[6][7]

References

  1. 1 2 3 4 5 6 7 Robert Newcomb, et al., Biochemistry 1998, 37, 15353–15362
  2. 1 2 3 4 Emmanuel Bourinet, et al., Biophysical Journal, Volume 81, July 2001 79–88
  3. 1 2 G Arroyo, et al., Eur J Pharmacol, 2003, 475: 11–8
  4. ↑ T Kimm, et al., J Neurosci, 2014, https://pubmed.ncbi.nlm.nih.gov/25009251/
  5. ↑ Wang, G, et al. (1999) J. Neurosci. 19, 9235
  6. ↑ Elizabeth A, et al., European Journal of Neuroscience, Vol. 25, pp. 3561–3569, 2007
  7. ↑ Gabriela Trevisan et al. Curr Neuropharmacol 2022 https://pubmed.ncbi.nlm.nih.gov/34259147
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