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Acid-Sensing Ion Channels and Synaptic Plasticity: A Revisit
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ming-Gang Liu, Michael X. Zhu, Tian-Le Xu
There are two major types of LTD co-existing in the hippocampus: NMDA receptor-dependent LTD (NMDAR-LTD) and metabotropic glutamate receptor-dependent LTD (mGluR-LTD). In the work of Mango et al. (2017), the authors demonstrated an age-dependent involvement of ASIC1a in mGluR-LTD in the hippocampus77. Specifically, pharmacological inhibition of ASIC1a by psalmotoxin 1 resulted in an attenuation of LTD induced by application of the group I mGluR agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or paired-pulse LFS in postnatal days 30–40 (P30–40) animals. However, psalmotoxin 1 did not affect both forms of mGluR-LTD in P13–18 animals. With respect to NMDAR-LTD, the same group further reported that ASIC1a is required for induction of electrical LTD by LFS or chemical LTD by bath application of NMDA. Interestingly, the role of ASIC1a in NMDAR-LTD is age-independent78. Together, the results point toward the conclusion that ASIC1a is a crucial player in hippocampal LTD. In contrast, our recent work with the multi-electrode array recording system failed to detect any effect of ASIC1a gene deletion or pharmacological blockade on LFS- or DHPG-evoked LTD in the hippocampus62. The exact reasons for the discrepancies are not clear. However, the divergence might be explained by differences in experimental conditions, such as the animal age, recording method, recording temperature and drug concentration. Therefore, more elaborative work is needed to clarify this issue.
Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASICs) in optic nerve crush model in rodents
Published in Current Eye Research, 2018
Dorota L. Stankowska, Brett H. Mueller, Hidehiro Oku, Tsunehiko Ikeda, Adnan Dibas
Amiloride (Sigma–Aldrich, St. Louis, MO, USA) stock solution (20 mM) dissolved in dimethyl sulfoxide was prepared. The stock solution of amiloride was subsequently diluted to a concentration of 2.4 mM with normal saline. Intraocular injection was carried out just before ONC. The 2.4 mM solution was injected intravitreally with a 30 G needle (Becton–Dickinson, Franklin Lakes, NJ) attached to a 10 µl Hamilton syringe under an operating microscope. Assuming an average vitreous chamber volume of the rat to be 60 µl in volume37, injecting 2.5 µl of 2.4 mM amiloride would give a final concentration of 100 µM (the concentration chosen based on previously published observation that it was the most consistently effective concentration for blocking inward currents in Muller cells.38) Vehicle-treated rats were given the same volume of saline. Sham-operated rats were used as controls. Psalmotoxin-1 was injected intravitreally following the same procedure as for amiloride. Final concentration of Psalmotoxin-1 in the rat eye was 1 µM. Vehicle-treated rats were given the same volume of PBS. Sham-operated eyes were used as controls.
Neuroprotective Effects of Psalmotoxin-1, an Acid-Sensing Ion Channel (ASIC) Inhibitor, in Ischemia Reperfusion in Mouse Eyes
Published in Current Eye Research, 2018
Adnan Dibas, Cameron Millar, Abraham Al-Farra, Thomas Yorio
Psalmotoxin-1, a 40-amino acid spider toxin isolated from Trinidad tarantula Psalmopoeus cambridgei, is a very potent and selective ASIC1a blocker.39 Psalmotoxin-1 (1 µg) was injected intravitreally 2 days before I/R while control mice received vehicle only (PBS). As shown in Figure 2I-L, psalmotoxin-1 did reduce expression of ASIC1a in RGC layer without affecting ASIC2 significantly at 24 h post-I/R. The exact mechanism of psalmotoxin-1-induced decrease in ASIC1a is not known but could involve endocytosis or other unknown mechanism. Next, we analyzed changes in ASIC1a and ASIC2 in retinas following I/R injury by western blot. As shown in Figure3A, I/R increased ASIC1a (2.2 ± 0.4 vs. sham, p < 0.05) and ASIC2 although showed a similar trend (1.9 ± 0.6, n = 4), changes were not statistically significant. However, the reason that immunohistochemistry analysis showed clear induction of ASIC2 but not by western blot could be due to different tissue’s processing for detection in both techniques. In immunohistochemistry analysis, it is near its native form, but in a western blot with SDS and heating, there may be subtle differences in antigen-binding sites between the two processed tissues that may explain the different results. Psalmotoxin-1 pretreatment decreased ASIC1a levels significantly (1.7 ± 0.1, p < 0.05 vs. PBS-I/R) without affecting changes in ASIC2 levels significantly (2.2 ± 0.6, Figure 3B, n = 4, vs. PBS-I/R). Densitometric analysis is shown in Figure 3C. This result however is consistent with the lack of significant changes in ASIC2 after psalmotoxin injection as assessed by immunohistochemistry (Figure 2J).
Advances in venom peptide drug discovery: where are we at and where are we heading?
Published in Expert Opinion on Drug Discovery, 2021
Taylor B. Smallwood, Richard J. Clark
With recent improvements in research techniques and processes, and a renewed focus for venom-derived drugs, the number of candidates in the development pipeline is increasing exponentially [2]. Current analytical technology now allows for the identification of venom peptides from species that provide only miniscule amounts of venom. Spiders, which produce less than 10 µL of venom, are considered the most successful terrestrial predators [2]. From the 42,000 species described to date [82], it is believed that their venom is likely to contain at least 10 million bioactive peptides [2]. Spider venom is abundant with disulfide-rich peptides, with inhibitory cysteine knot (ICK) peptides dominating most spider venom peptidomes [83]. This family of peptides possesses a unique structural motif consisting of a triplet-stranded antiparallel β-sheet stabilized by three disulfide bridges [84]. A knot is formed when two of the disulfide bonds create a ring that is penetrated by the third disulfide bond. The knotted topology creates a very stable structure that is resistant to heat denaturation and proteolysis [85]. Some ICK peptides exhibit unique pharmacological properties by modulating key membrane proteins such as the voltage-gated sodium channels (Nav1.1–1.9) [86]. The Nav channels are essential to the initiation and propagation of action potentials in excited cells and are thought to play a key role in the pathogenesis of many neurological disorders including chronic pain and epilepsy. Several species of tarantulas possess venom containing ICK peptides, which show potential to treat a range of neurological disorders. Protoxin-II [87], Huwentoxin IV [88], µ-theraphotoxin-Pn3a [89], Ceratotoxin-1 [90], and GpTx-1 [91] are ICK peptides currently in preclinical development as potential future analgesics. Other tarantula toxins like 40-residue Psalmotoxin 1 (PcTx1) [92] and the 76-residue Hi1A toxin [93] from the Australian funnel web (Hadronyche infensa) are reported to potently inhibit the ASIC1a ion channel. ASIC1a is a primary acid sensor in mammalian brain that is considered as a key mediator of stroke-induced neuronal damage [93]. Compared to PcTx1, Hi1a is a slightly more selective and potent inhibitor of ASIC1a, and is a potential lead for the development as a neuroprotective agent as it strongly attenuates brain damage after a stroke [93,94].