Interaction of α9α10 Nicotinic Receptors With Peptides and Proteins From Animal Venoms

Tsetlin, Victor; Haufe, Yves; Safronova, Valentina; Serov, Dmitriy; Shadamarshan, Pranavkumar; Son, Lina; Shelukhina, Irina; Kudryavtsev, Denis; Kryukova, Elena; Kasheverov, Igor; Nicke, Annette und Utkin, Yuri (23. Dezember 2021): Interaction of α9α10 Nicotinic Receptors With Peptides and Proteins From Animal Venoms. In: Frontiers in Cellular Neuroscience, Bd. 15, 765541

Abstract

Unlike most neuronal nicotinic acetylcholine receptor (nAChR) subunits, α7, α9, and α10 subunits are able to form functional homo- or heteromeric receptors without any β subunits. While the α7 subtype is widely distributed in the mammalian brain and several peripheral tissues, α9 and α9α10 nAChRs are mainly found in the cochlea and immune cells. α-Conotoxins that specifically block the α9α10 receptor showed anti-nociceptive and anti-hyperalgesic effects in animal models. Hence, this subtype is considered a drug target for analgesics. In contrast to the α9α10-selective α-conotoxins, the three-finger toxin α-bungarotoxin inhibits muscle-type and α7 nAChRs in addition to α9α10 nAChRs. However, the selectivity of α-neurotoxins at the α9α10 subtype was less intensively investigated. Here, we compared the potencies of α-conotoxins and α-neurotoxins at the human α9α10 nAChR by two-electrode voltage clamp analysis upon expression in Xenopus oocytes. In addition, we analyzed effects of several α9α10-selective α-conotoxins on mouse granulocytes from bone marrow to identify possible physiological functions of the α9α10 nAChR subtype in these cells. The α-conotoxin-induced IL-10 release was measured upon LPS-stimulation. We found that α-conotoxins RgIA, PeIA, and Vc1.1 enhance the IL-10 expression in granulocytes which might explain the known anti-inflammatory and associated analgesic activities of α9α10-selective α-conotoxins. Furthermore, we show that two long-chain α-neurotoxins from the cobra Naja melanoleuca venom that were earlier shown to bind to muscle-type and α7 nAChRs, also inhibit the α9α10 subtype at nanomolar concentrations with one of them showing a significantly slower dissociation from this receptor than α-bungarotoxin.

• Dokumententyp: Zeitschriftenartikel
• Keywords: Nicotinic acetylcholine receptor; α9α10 subtype; Xenopus laevis oocytes; α–neurotoxin; α-conotoxin; granulocytes; interleukin-10; inflammation
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch