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]

References

  1. ^ a b c d e f g Newcomb, Robert; et al. (1998-11-01). "Selective Peptide Antagonist of the Class E Calcium Channel from the Venom of the Tarantula Hysterocrates gigas". Biochemistry. 37 (44): 15353–15362. doi:10.1021/bi981255g. ISSN 0006-2960. PMID 9799496.
  2. ^ a b c d Bourinet, Emmanuel; et al. (2001). "Interaction of SNX482 with Domains III and IV Inhibits Activation Gating of α1E (CaV2.3) Calcium Channels". Biophysical Journal. Elsevier BV. 81 (1): 79–88. Bibcode:2001BpJ....81...79B. doi:10.1016/s0006-3495(01)75681-0. ISSN 0006-3495. PMC 1301493. PMID 11423396.
  3. ^ a b Arroyo, G (2003-08-15). "SNX482 selectively blocks P/Q Ca2+ channels and delays the inactivation of Na+ channels of chromaffin cells". European Journal of Pharmacology. Elsevier BV. 475 (1–3): 11–18. doi:10.1016/s0014-2999(03)02084-3. ISSN 0014-2999. PMID 12954354.
  4. ^ Kimm, T.; Bean, B. P. (2014-07-09). "Inhibition of A-Type Potassium Current by the Peptide Toxin SNX-482". Journal of Neuroscience. Society for Neuroscience. 34 (28): 9182–9189. doi:10.1523/jneurosci.0339-14.2014. ISSN 0270-6474. PMC 4087201. PMID 25009251.
  5. ^ Wang, Gang; et al. (1999-11-01). "An R-Type Ca2+Current in Neurohypophysial Terminals Preferentially Regulates Oxytocin Secretion". The Journal of Neuroscience. Society for Neuroscience. 19 (21): 9235–9241. doi:10.1523/jneurosci.19-21-09235.1999. ISSN 0270-6474. PMC 6782897. PMID 10531427.
  6. ^ Trevisan, Gabriela; Oliveira, Sara Marchesan (2022). "Animal Venom Peptides Cause Antinociceptive Effects by Voltage-gated Calcium Channels Activity Blockage". Current Neuropharmacology. Bentham Science Publishers Ltd. 20 (8): 1579–1599. doi:10.2174/1570159x19666210713121217. ISSN 1570-159X. PMC 9881091. PMID 34259147.
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