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Eukaryotic Mechanosensitive Ion Channels
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Evidence from different independent investigators demonstrated that Piezo channels are specialized force transducers activated by any physiological membrane tension generated by diverse mechanical forces, such as shear stress (blood flow), stiffness (bone) and stretch (lung) [3,24]. The most common in vitro mechanical stimulations are “stretch” and “poke” in combination with patch-clamp electrophysiology. In the “stretch” model, the membrane is stimulated using a high-speed pressure clamp, which results in highly reproducible pressure–response relationships. In the “poke” model, the membrane is indented with a blunt glass probe, leading to larger current amplitudes [24]. Piezo1, but not Piezo2, can also be activated by chemical activators, including Yoda1 [25], Jedi1/Jedi2 [26], and intrinsically by single strand RNAs [27]. Piezo channels can be inhibited by non-specific blockers, including ruthenium red, gadolinium ion, and the spider toxin GsMTx4 [22,28,29].
Antinociceptive peptides from venomous arthropods
Published in Toxin Reviews, 2023
Jessica A. I. Muller, Lai Y. Chan, Monica C. Toffoli-Kadri, Marcia R. Mortari, David J. Craik, Johannes Koehbach
Well studied peptides include, for example, GpTx-1, GsMTx4, PcTx1, huwentoxins (HwTx), hainantoxins (HNTX), μ-TRTX-Pn3a, protoxins and PnTx. All these peptides have been characterized on validated pain targets in vitro and show analgesic potential in in vivo assays and have recently been reviewed (Akef 2018, Hamad et al.2018, Wu et al.2018, Cardoso and Lewis 2019, Wu et al.2019, Lauria et al.2020, Neff and Wickenden 2021). On the other hand, many peptides are not thoroughly studied, being described only by individual electrophysiological or animal assays (Table 1). Although peptides that block or reduce pain signal transmission at validated pain targets in vitro have the potential to reduce pain in vivo, assays with animal models are needed to verify this activity, and many peptides lack this in vivo information. Likewise, in vivo assays alone are insufficient, as they cannot identify the mechanism or target by which the peptide exhibits its antinociceptive effects. It is therefore imperative to corroborate observed in vivo or in vitro activities. Therefore, we recommend referring to compounds that lack in vivo data as ‘potential analgesic peptides’ (see Sections 2.2, 3.2 and 4.2). Peptides that have been extensively studied will not be discussed in detail here and we focus on peptides that have not been reviewed before.
Emerging drug targets for sickle cell disease: shedding light on new knowledge and advances at the molecular level
Published in Expert Opinion on Therapeutic Targets, 2023
Psickle inhibitors: The Psickle-like pathway activated in deoxygenated sickle cells was found to be partially inhibited by band 3 inhibitors such as 4,4′-diisothiocyano-2,2′-stilbenedisulphonate (DIDS) and dipyridamole [38,42]. This finding, together with the fact that mutated band 3 molecules may function as ion channels [214], has been partly responsible for the hypothesis that Psickle might be a manifestation of the anion exchanger. More efficacious compounds were lacking, however. Normal red cells also show a cation conductance, activated physiologically by mechanical distortion, for example by shear stress [215,216], rather than pathologically by the presence of rigid HbS polymers and which is permeable to Ca2+. The mechanosensitive channel PIEZO1 is currently the most likely contender for this pathway in red cells, and, by extension, a candidate for Psickle. However, although some studies have linked common PIEZO1 alleles to SCD patients [217], others found no correlation with Psickle-like activity [218]. The PIEZO1 entity comprises a very large protein, comprising about 2500 amino acids and a mass of some 300 kDa, with a complex mode of activation and kinetic behavior. Small molecule inhibitors of PIEZO1 exist, like the naturally occurring tarantula venom GsMTx4 and the synthetic partial antagonist DOOKU1 [219], and have similar actions against the Psickle permeability of deoxygenated sickle cells. No compounds have yet been targeted specifically at the channel in sickle cells. Nonetheless, increased understanding of how this system becomes activated and inactivated has the potential for new effective drugs against SCD.