A novel single knot peptide Hc3a modulates ASIC1a desensitisation

Acid-sensing ion channels (ASICs) are proton-gated sodium channels widely expressed in various tissues, including the central and peripheral nervous systems. ASICs play crucial roles in numerous physiological processes, such as pain sensation, fear conditioning, synaptic plasticity, learning, and memory. Additionally, they have been implicated in several pathological conditions, including neurodegeneration (e.g., Parkinson’s, Alzheimer’s) and ischemic stroke, where the extracellular space becomes acidic due to a lack of oxygen and nutrients.

Various small-molecule compounds and biopharmaceuticals have been developed to modulate the activity of ASICs, either by blocking or enhancing their function. These agents are being explored for the treatment of pain, stroke, and certain mental health conditions, showcasing the therapeutic potential of targeting ASICs in disease management.

Peptides in general, and venom-derived toxins in particular, have long been recognized as a valuable source for pharmacologically targeting ion channels, including ASICs. The spider venom-derived peptides PcTx1 and Hi1a are two of the most potent ASIC1a inhibitors known and have been instrumental in advancing our understanding of the structure, function, and biological roles of ASICs.

A recent article introduced a novel single inhibitor cystine knot peptide, Hc3a, from the Australian funnel-web spider Hadronyche cerberea, which shares sequence similarities with previously identified peptides but exhibits a distinct pharmacological profile against ASIC1a.

Hc3a is distinctive in its ability to bind to various conformational states of ASIC1a—closed, open, and desensitized states—with varying binding affinities, significantly impacting the channel’s desensitization. Using two-electrode voltage clamp as well as automated patch clamp techniques (Patchliner), the researchers showed that the peptide slows down the desensitization of proton-induced ASIC1a currents, stabilizing the open state of ASIC1a, a feature not prominently observed with other ASIC1a modulators. Also, the research explored the subtype-selectivity of Hc3a, revealing its potent and specific action on ASIC1a over other ASIC subtypes.

Mutagenesis studies showed that introducing specific residues from the PcTx1 peptide into Hc3a did not replicate PcTx1’s inhibitory effect on ASIC1a, indicating distinct pharmacophores between these peptides despite their sequence similarities.

In summary, this study identified a new peptide from the venom of H. cerberea with unique modulatory activity on ASIC1a. The fact that Hc3a seems to stabilize a different functional state than any other spider venom ASIC1a modulator makes it a unique tool for studying ASIC1a gating.

For more details, please refer to the paper here: https://www.sciencedirect.com/science/article/pii/S0006295224001588

Discover more about the Patchliner, the most versatile automated patch clamp system on the market: https://www.nanion.de/products/patchliner/