Toxin Name δ-theraphotoxin-Hm1a
Source Species Heteroscodra  maculata (Togo starburst tarantula)
Toxin Group Theraphotoxin
Description δ-theraphotoxin-Hm1a is a gating modifier toxin that inhibits inactivation of the mammalian voltage-gated sodium channel Nav1.1. When tested against human Nav1.1–1.8 α subunits heterologously expressed in Xenopus oocytes, the toxin inhibited inactivation of Nav1.1 (EC50 = 38 ± 6 nM), with substantially weaker effects on Nav1.2 (EC50 = 236 nM) and Nav1.3 (EC50 = 220 nM), and no effect on Nav1.4–1.8 at concentrations up 1 μM. The toxin inhibits several subtypes of voltage-gated potassium channel with significantly lower potency than its effects on Nav1.1. It has little effect on Kv1.1-Kv1.6 and Kv3.4, but it is a moderately potent blocker of Kv2.1, Kv2.2, Kv4.1, Kv4.2, and Kv4.3. The toxin is a homolog of δ-theraphotoxin-Hm1b, which was isolated from the venom of the same species.

In mouse trigeminal neurons, the toxin enhances action potential firing and prolongs action potential duration without altering the resting membrane potential, consistent with inhibition of Nav1.1 inactivation. In an ex vivo skin-nerve preparation the toxin enhances firing of mechanosensitive Aδ fibres during mechanical stimulus. When injected into mouse hindpaw, the toxin elicits an immediate and robust nocifensive response. However, intraplantar injection of toxin does not cause neurogenic inflammation or alter sensitivity to heat, indicative of a modality-specific effect on mechanosensitive neurons.

Given that chronic mechanical hypersensitivity underlies the development of abdominal pain in patients with irritable bowel syndrome, the toxin was tested in an ex vivo gut-nerve preparation. In healthy mice, the toxin evoked spiking in a subset of high-threshold mechanosensitive colonic fibers that express functional Nav1.1 channels. In mice with chronic visceral mechanical hypersensitivity, which have an elevated baseline spiking frequency, the toxin increased spiking frequency even further, suggesting a role for Nav1.1 in visceral mechanical pain.

Similar to scorpion α-toxins that inhibit sodium channel inactivation, the toxin binds to the voltage sensor in channel domain IV. The binding affinity and subtype selectivity of the toxin is determined by residues within both the S1-S2 and S3-S4 loops of the domain IV voltage sensor.
Discovered 2001
Sex: female, Prosoma length: 20mm
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This toxin last updated on Nov 02, 2016

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Protein Information
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