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µ-TRTX-Ca1a: a novel neurotoxin from Cyriopagopus albostriatus with analgesic effects
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µ-TRTX-Ca1a: a novel neurotoxin from Cyriopagopus albostriatus with analgesic effects
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Journal Article
µ-TRTX-Ca1a: a novel neurotoxin from Cyriopagopus albostriatus with analgesic effects
2019
Overview
Human genetic and pharmacological studies have demonstrated that voltage-gated sodium channels (VGSCs) are promising therapeutic targets for the treatment of pain. Spider venom contains many toxins that modulate the activity of VGSCs. To date, only 0.01% of such spider toxins has been explored, and thus there is a great potential for discovery of novel VGSC modulators as useful pharmacological tools or potential therapeutics. In the current study, we identified a novel peptide, µ-TRTX-Ca1a (Ca1a), in the venom of the tarantula
Cyriopagopus albostriatus
. This peptide consisted of 38 residues, including 6 cysteines, i.e. IFECSISCEIEKEGNGKKCKPKKCKGGWKCKFNICVKV. In HEK293T or ND7/23 cells expressing mammalian VGSCs, this peptide exhibited the strongest inhibitory activity on Na
v
1.7 (IC
50
378 nM), followed by Na
v
1.6 (IC
50
547 nM), Na
v
1.2 (IC
50
728 nM), Na
v
1.3 (IC
50
2.2 µM) and Na
v
1.4 (IC
50
3.2 µM), and produced negligible inhibitory effect on Na
v
1.5, Na
v
1.8, and Na
v
1.9, even at high concentrations of up to 10 µM. Furthermore, this peptide did not significantly affect the activation and inactivation of Na
v
1.7. Using site-directed mutagenesis of Na
v
1.7 and Na
v
1.4, we revealed that its binding site was localized to the DIIS3-S4 linker region involving the D816 and E818 residues. In three different mouse models of pain, pretreatment with Cala (100, 200, 500 µg/kg) dose-dependently suppressed the nociceptive responses induced by formalin, acetic acid or heat. These results suggest that Ca1a is a novel neurotoxin against VGSCs and has a potential to be developed as a novel analgesic.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Analgesics - isolation & purification
/ Animals
/ Arthropod Proteins - isolation & purification
/ Arthropod Proteins - metabolism
/ Arthropod Proteins - pharmacology
/ Biomedical and Life Sciences
/ Ganglia, Spinal - drug effects
/ Humans
/ NAV1.7 Voltage-Gated Sodium Channel - genetics
/ NAV1.7 Voltage-Gated Sodium Channel - metabolism
/ Neurotoxins - isolation & purification
/ Peptides
/ Sodium channels (voltage-gated)
/ Spider Venoms - isolation & purification
/ Spider Venoms - pharmacology
/ Vaccine
/ Venom
/ Voltage-Gated Sodium Channel Blockers - isolation & purification
