Evidence 1
Activity
Activity
Neurotoxin
FUNCTION: Gating-modifier toxin that targets both voltage-gated sodium and calcium channels, with described activities on hNav1.1/SCN1A, hNav1.2/SCN2A, hNav1.3/SCN3A, hNav1.4/SCN4A, hNav1.5/SCN5A, hNav1.6/SCN8A, h/m/r Nav1.7/SCN9A, hNav1.9/SCN11A, hCav1.2/CACNA1C, hCav1.3/CACNA1D, hCav2.1/CACNA1A and hCav2.2/CACNA1B channels (PubMed:28106092, PubMed:31234412, PubMed:33584315, PubMed:35858123). According to Deuis and colleagues, shows a preferential activity on Nav1.7/SCN9A (Nav1.7/SCN9A (IC(50)=0.9-4.4 nM)) (PubMed:28106092). Another study shows a much less potent activity on Nav1.7/SCN9A (IC(50)=1457 nM) (PubMed:31234412). Also shows potent to moderate effects on hNav1.1/SCN1A (IC(50)=37 nM), hNav1.2/SCN2A (IC(50)=124 nM), hNav1.3/SCN3A (IC(50)=210 nM), hNav1.4/SCN4A (IC(50)=144 nM), hNav1.5/SCN5A (IC(50)=800 nM), hNav1.6/SCN8A (IC(50)=129 nM), hNav1.9/SCN11A (IC(50)=2427 nM) (PubMed:28106092). On Nav1.7/SCN9A, the toxin acts by shifting the voltage-dependence of activation to more depolarized potentials, whereas it does not cause significant effect on the voltage-dependence of activation on other sodium channels (PubMed:28106092). Minor effects are observed on the voltage-dependence of steady-state fast inactivation for all sodium channels tested (Nav1.1/SCN1A-Nav1.7/SCN9A) (PubMed:28106092). Shows a specific interaction with the S3-S4 linkers in DII and DIV domains of Nav1.7/SCN9A (PubMed:28106092). Also shows inhibitory activity on calcium channels (PubMed:35858123). Rat DRG neuron high voltage-activated (HVA) calcium currents (ICa) are inhibited by 55% by high concentration (10 uM) of this toxin (PubMed:35858123). In addition, mCav1.2, rCav1.3, hCav2.1, and hCav2.2 channels are reversibly inhibited (60-80% inhibition by 10 uM of toxin) (PubMed:35858123). The toxin inhibits hCav2.2 (IC(50)=3.71 uM) by inducing a hyperpolarizing shift in steady-state inactivation, without apparent changes in channel activation (PubMed:33584315). The toxin also inhibits Cav3.3/CACNA1I channels, but it modifies its gating through a depolarizing shift in the voltage dependence of activation thus decreasing hCav3.3-mediated currents (IC(50)=960 nM) (PubMed:35858123). May also stabilize the closed/resting state of Cav3.3 (PubMed:35858123). Recovers 1.5-fold faster from inactivation, compared to control (PubMed:35858123). Shows a specific interaction to the S3-S4 region of DII domain voltage sensor of Cav3.3/CACNA1I (PubMed:35858123). In vivo, when tested on a mouse model of pain induced by Nav1.7 activation, the toxin dose-dependently reduces pain behavior (PubMed:28106092). In addition, in rodent pain models, co-administration of the toxin with sub-therapeutic doses of opioids results in significant analgesia/anti-allodynia, arguing for synergistic analgesic effects (PubMed:28106092, PubMed:31335646). {ECO:0000269|PubMed:28106092, ECO:0000269|PubMed:31234412, ECO:0000269|PubMed:31335646, ECO:0000269|PubMed:33584315, ECO:0000269|PubMed:35858123}.
Target
voltage-gated sodium channel (Nav)
voltage-gated calcium channel (Cav)
Source & Reference
NA
UniProtKB/Swiss-Prot Tox-Prot
Other
Pamphobeteus nigricolor (Giant blue bloom tarantula)
Neurotoxin
Ion channel impairing toxin
Voltage-gated sodium channel impairing toxin
Gating-modifier toxin that targets both voltage-gated sodium and calcium channels, with described activities on hNav1.1/SCN1A, hNav1.2/SCN2A, hNav1.3/SCN3A, hNav1.4/SCN4A, hNav1.5/SCN5A, hNav1.6/SCN8A, h/m/r Nav1.7/SCN9A, hNav1.9/SCN11A, hCav1.2/CACNA1C, hCav1.3/CACNA1D, hCav2.1/CACNA1A and hCav2.2/CACNA1B channels (PubMed:28106092, PubMed:31234412, PubMed:33584315, PubMed:35858123). According to Deuis and colleagues, shows a preferential activity on Nav1.7/SCN9A (Nav1.7/SCN9A (IC(50)=0.9-4.4 nM)) (PubMed:28106092).
Mu-theraphotoxin-Pn3a (Mu-TRTX-Pn3a)
spider
Neurotoxin 10 (Hwtx-1) family, 28 (Jztx-11) subfamily
Evidence at protein level
3D-structure
Direct protein sequencing
Disulfide bond
Ion channel impairing toxin
Knottin
Neurotoxin
Pharmaceutical
Secreted
Toxin
Voltage-gated sodium channel impairing toxin
TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305|PubMed:28106092}.