Hc3a is a peptide found in the venom of the Australian funnel web spider, it works on the acid-sensing ion channel (ASIC1), a proton-gated sodium channel. Hc3a works on the desensitisation mechanisms of ASCI1a.
 Hc3a neurotoxin | |
| Source | Australian funnel Web spider |
|---|---|
| Amino acids | NECIRKWLSCVDRKNDCCEGLECWKRRGNKSSVCVPIT |
| Target | ASCI1 |
| Family | Inhibitor cysteine knot |
Source
editHc3a is a peptide derived from the venom gland transcriptome of the Australian Funnel web spider Hadronyche cerberea (H. cerbrea).[1]
Chemistry
editHc3a is a single inhibitor cystine knot (ICK) peptide consisting of 38 amino acids that resemble other single and double ICKs such as PcTx1 and Hm3a, having 59% and 63% in common, respectively and Hi1a.[1] It is also identical to parts of Hc1a, a double ICK also found in H. cerbrea venom; the first 23 amino acids of Hc3a are identical to the N-terminus of Hc1a and the other 15 are almost identical to the C-terminus with only one amino acid being different.[1] This leads to a Amino acid sequence of:
NECIRKWLSCVDRKNDCCEGLECWKRRGNKSSVCVPIT
The structure of Hc3a is a hydrophobic patch surrounded by charged residues, showing an identicl fold to PcTx1. It contains three disulphide bridges that give rise to a tightly knotted structure with 3 folds. Despite these similarities Hc3a seems to have a different mechanism of action than other known peptides that work on the same channel.[1]
Target
editHc3a, in a similar way to PcTx1, binds to the acidic pocket of ASIC1a, and particularly slows the desensitisation of the receptor.[1] It also has weak effects on ASIC1b. ASICs are ligand-gated ion channels, specifically sensitive to positively charged ions with a high concentration outside of the cell, like sodium. ASIC channels open when hydrogen binds to it.[1] For this to happen, there needs to be an increase in hydrogen, which occurs when the pH is acidic, something that is seen when the pH is a lower level than its resting state (7.4).[1] Expression of ASIC1 is mainly in the central nervous system and the sensory neurons of the dorsal root ganglia.[2] ASIC1 has different conformational states, namely open, closed, or desensitised.[3]
Mode of action
editHc3a has different effects depending at which of the three states of the ASCI1a it binds. It may bind to the open or closed state Hc3a, which leads to a potentiation of currents by slowing down desensitisation gating. When Hc3a binds to the desensitised state, on the other hand, it can stabilise the desensitised state leading to inhibition of acidic pH-envoked currents, however this only happens when Hc3a is applied directly at this state.[1]
The effects of Hc3a on ASIC1a vary depending on the pH of the environment, with stronger effects at acidic pH levels. At neutral or slightly basic pH (~7.6), Hc3a weakly potentiates the peak current and slows the desensitisation of ASIC1a, meaning that once the channel opens in response to a proton influx, it stays open for longer before closing down. At more acidic pH levels (~7.3), Hc3a begins to show potent inhibition of the peak current. This suggests that at lower pH, where ASIC1a is more likely to be activated, Hc3a interacts with the channel in a way that limits its full activation. At more acidic pH- levels of around 7.15 Hc3a can act as a weak direct agonist, sustaining the opening of the channel. This effect is relatively weak, because it only reaches around 20% of normal proton-induced current. This suggests that under extremely acidic conditions, Hc3a can directly bind and open the channel, mimicking the effect of protons. Hc3a further leads to an upward shift of pH levels to reach the same amount of channel desensitisation, leading to a prolonged opening of ASIC1a. Overall, Hc3a has only limited potency at all states and pH levels, leading to a weak efficacy for this toxin.[1]
Therapeutic use
editDue to its efficacy and its dependency on the state of the channel, Hc3a is not being used as a therapeutic tool. ASIC1 channels play a role in pain signaling, mostly during inflammatory and neuropathic pain, as well as synaptic transmission, learning, and memory.[4] Additionally, inhibition of ASIC1a has been demonstrated to have neuroprotective effects during an ischemic stroke.[4] The ability of Hc3a to enhance desensitisation, when applied to a desensitised channel, could help protect neurons from cell death during a stroke.[1]
References
edit- ^ a b c d e f g h i j Budusan, Elena; Payne, Colton D.; Gonzalez, Tye I.; Obergrussberger, Alison; Becker, Nadine; Clark, Richard J.; Johan Rosengren, K; Rash, Lachlan D.; Cristofori-Armstrong, Ben (2024-10-01). "The funnel-web spider venom derived single knot peptide Hc3a modulates acid-sensing ion channel 1a desensitisation". Biochemical Pharmacology. Enna Legacy of Excellence. 228: 116175. doi:10.1016/j.bcp.2024.116175. ISSN 0006-2952. PMID 38552850.
- ^ Wemmie, John A.; Chen, Jianguo; Askwith, Candice C.; Hruska-Hageman, Alesia M.; Price, Margaret P.; Nolan, Brian C.; Yoder, Patrick G.; Lamani, Ejvis; Hoshi, Toshinori; Freeman, John H.; Welsh, Michael J. (April 2002). "The Acid-Activated Ion Channel ASIC Contributes to Synaptic Plasticity, Learning, and Memory". Neuron. 34 (3): 463–477. doi:10.1016/s0896-6273(02)00661-x. ISSN 0896-6273. PMID 11988176.
- ^ Gründer, Stefan; Pusch, Michael (2015-07-01). "Biophysical properties of acid-sensing ion channels (ASICs)". Neuropharmacology. Acid-Sensing Ion Channels in the Nervous System. 94: 9–18. doi:10.1016/j.neuropharm.2014.12.016. ISSN 0028-3908. PMID 25585135.
- ^ a b Heusser, Stephanie A.; Pless, Stephan A. (December 2021). "Acid-sensing ion channels as potential therapeutic targets". Trends in Pharmacological Sciences. 42 (12): 1035–1050. doi:10.1016/j.tips.2021.09.008. ISSN 0165-6147. PMID 34674886.