Overview
Alomone Labs µ-TRTX-Tsp1a inhibits NaV1.7 channel currents heterologously expressed in Xenopus oocytes.A. Representative time course of µ-TRTX-Tsp1a (#STT-500) inhibition of NaV1.7 channels current. Membrane potential was held at -80 mV, current was elicited by a 100 ms voltage step to 0 mV every 10 sec, and significantly inhibited by application of 150 nM µ-TRTX-Tsp1a (green).
B. Superimposed traces of NaV1.7 channel currents in the absence (control) and presence (green) of 150 nM µ-TRTX-Tsp1a (taken from the recording in A).
μ-theraphotoxin-Tsp1a (Tsp1a) is a 28 amino acid peptidyl toxin originally isolated from the venom of the Thrixopelma spec. (Peru) spider venom. Tsp1a is a potent (IC50 = 10 nM) and highly specific inhibitor of NaV1.7 channels, with a selectivity of >100-fold over hNaV1.3−hNaV1.6 and hNaV1.8, 45-fold over hNaV1.1, and 24-fold over hNaV1.21.
Tsp1a is a gating modifier toxin that inhibits hNaV1.7 by stabilizing the channel in its inactivated state, inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation1.
Spider peptides modulate an array of ion channels and receptor proteins. Knottins, which are a subtype of spider peptides, are also referred to as inhibitor cystine knot (ICK) peptides. ICK peptides harbor a disulfide-rich structural motif that forms a “knot”, which confers high structural, thermal, and proteolytic stability. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum1.
NaV1.7 is expressed in the PNS, dorsal root ganglia neurons, visceral sensory neurons, olfactory sensory neurons, trigeminal ganglia, and sympathetic neurons. Gain-of-function mutations in SCN9A, the gene encoding NaV1.7, have been identified in patients with various pain disorders, such as inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD), small fiber neuropathy (SFN), and painful diabetic peripheral neuropathy. Nav 1.7 loss-of-function mutations lead to a congenital indifference to pain2,3. Tsp1a toxin was shown to reduce visceral hypersensitivity in a model of irritable bowel syndrome. This suggests that pharmacological inhibition of hNaV1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain1.
