Ant Toxins with Subtype Precision

New Reagents for Na_V Channel Modulation

Voltage-gated sodium (Na_V) channels are having a moment. Once the domain of basic electrophysiology, they’re now front and centre in efforts to develop safer pain therapies, dissect neuronal excitability, and untangle the mechanics of neurodegeneration. Each subtype – Na_V1.1 through Na_V1.9 – plays a distinct role in the body’s excitable tissues, from seizure thresholds in the cortex to signal fidelity in nociceptors. And with growing access to subtype-selective modulators, researchers can now test those roles with unprecedented precision.

Why does that matter? Because modulating individual Na_V isoforms could unlock entirely new therapeutic strategies. Case in point: Na_V1.8, a tetrodotoxin (TTX)-resistant channel heavily expressed in peripheral sensory neurons, has become a promising non‑opioid target for treating pain. The drug Suzetrigine (VX‑548), which selectively inhibits Na_V1.8, has completed Phase 3 trials for acute pain (e.g. post‑surgery) and been approved for moderate‑to‑severe acute pain in the US (1). Studies in neuropathic or chronic pain are ongoing, but large‑scale clinical validation in that area is still pending.

But this is where venom peptides come in. Ants have spent millions of years evolving high-potency chemical tools to disrupt vertebrate sodium signalling, often with exquisite selectivity. To build on this, we’ve recently introduced five synthetic ant toxins that modulate specific Na_V channel subtypes. The five synthetic toxins described below give you subtype-tuned, mechanistically distinct ways to interrogate Na_V1.6–Na_V1.9 activity in neurons, with clear readouts and validated cellular targets.

Ectatotoxin-Rm4a

Ectatotoxin-Rm4a (#STR-010) (Rm4a) is a 26-residue peptide isolated from the venom of Rhytidoponera metallica (Australian green-headed ant) and delays inactivation of Na_V1.6 and Na_V1.7 channels. In mice, Rm4a injections produced the same slow-onset but persistent pain behaviours that people report after a sting (2). At the cellular level, it hits TTX-sensitive sodium channels hard: in DRG neurons, it drove sustained calcium influx, and in HEK293 cells expressing human channels, it kept Na_V1.7 currents open, with a clear hyperpolarising shift in activation. It shows its strongest activity at Na_V1.6 but also modulates Na_V1.7 with weaker effects on Na_V1.8 and Na_V1.9 (Figure 1). For researchers, this makes Rm4a a sharp tool for probing Na_V1.6 and Na_V1.7 function, pain signalling, and the broader role of TTX-sensitive channels in sensory neurons.

Myrmicitoxin-Pm1a and -Pm2a

Myrmicitoxin-Pm1a (#STP-030) (Pm1a) is a 24-residue peptide while Myrmicitoxin-Pm2a (#STP-040) (Pm2a) is a 27-residue peptide, both derived from Pogonomyrmex maricopa (Maricopa harvester ant) venom. Pm1a and Pm2a were tested in mice, sensory neurons, and HEK293 cells to see why this sting is so memorable (3). In mice, each peptide induced persistent pain behaviours that were abolished by tetrodotoxin, confirming action on Na_V channels. In DRG neurons, nanomolar doses produced sustained Ca²⁺ signals through TTX-sensitive Na_V channels. In HEK293 cells, both shifted activation of Na_V1.6 and Na_V1.7 and drove persistent currents that left the channels in a hyper-excitable state. Pm1a acted at submicromolar concentrations. Pm2a was more potent, with a slow off-rate and persistent effects after washout, and it also modulated Na_V1.8 and Na_V1.9. Neither peptide showed activity in insects, marking them as vertebrate-specific defensive toxins. Based on these data, Pm1a and Pm2a may very well represent a new class of Na_V channel modulator.

In experimental settings, Pm1a and Pm2a provide selective probes for Na_V1.6 and Na_V1.7, tools for dissecting persistent currents in pain signalling, and test agents for both TTX-sensitive and resistant sodium channels.

Ta3a Toxin

Ta3a Toxin (#STT-020) (Ta3a) is a 29-residue peptide from Tetramorium africanum (African ant) venom that induces sustained sodium current in Na_V1.7-expressing cells. In DRG neurons, Ta3a drove sustained Ca²⁺ signals that dropped sharply with TTX, placing the effect on TTX-sensitive Na_V channels (4). Mechanistically, whole-cell recordings showed Ta3a converts hNa_V1.7 from a fast-inactivating current to a persistent, non-inactivating one, with single-channel data showing a big jump in open probability. Follow-up work went deeper: Ta3a causes a strong hyperpolarising shift in activation threshold, induces constitutive activity even at voltages where channels are usually silent, and shifts the apparent reversal potential by altering local extracellular Na⁺ via surface-charge effects. The authors propose Ta3a stabilises S4 voltage sensors in an activated configuration, effectively creating an “ionic bilayer” at the membrane that depolarises cells and lowers the voltage needed to fire.

Ta3a serves as a precise way to impose sustained Na_V1.7 activity without pore-forming artefacts, ideal for mapping window/persistent currents, testing TTX-sensitive pain pathways, and probing how membrane surface potential shapes channel gating. Pair it with TTX or selective Na_V blockers for mechanistic controls and use it in HEK/DRG patch-clamp or calcium-imaging workflows when you need a reliable, reversible driver of neuronal hyperexcitability.

Poneratoxin

Poneratoxin (#STP-360) (PoTx) is the 25-residue peptide behind the infamous sting of Paraponera clavata (the bullet ant). In human SH-SY5Y and ND7/23 neuron-like cells, functions as a persistent Na_V agonist beyond the usual Na_V1.6/1.7 story – it also activates Na_V1.2 and Na_V1.3, slows inactivation, reduces peak current, and drives a sustained intracellular Ca²⁺ rise. TTX shut these effects down, confirming a Na_V-dependent mechanism. PoTx alone did not induce cell death even at 40 µM over 24 h, but when the Na⁺/K⁺-ATPase was blocked with ouabain to remove the sodium safety valve, PoTx became sharply excitotoxic, with cell swelling and apoptosis – defined, controllable conditions for modelling sodium-driven injury. Multi-omics then mapped the downstream consequences: PoTx triggered transcriptomic and proteomic signatures of cell-cycle arrest and senescence, increased tau-Ser396 phosphorylation via PI3K–Akt/GSK-3 and CDK5 and suppressed ULK1 and other plasticity/autophagy markers; blocking Na_V channels with TTX largely erased these changes.

PoTx is a practical way to impose persistent Na_V activation without immediate cytotoxicity, to probe coupling between Na_V gating, Ca²⁺ overload and neurodegenerative signalling, and to screen neuroprotective interventions in an ouabain-sensitised excitotoxicity model alongside standard controls like veratridine (5).

An ANTirely New Approach to Na_V Modulation

These five peptides give you new ways to probe fast inactivation, persistent current, and Na_V subtype selectivity across sensory and central neurons. With synthetic availability, clean formulation, and validated targets, they are ready for integration into lab workflows across pain, neurophysiology, and degenerative disease models.