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

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.

αO-Conotoxin GeXIVA[1,2] Reduced Neuropathic Pain and Changed Gene Expression in Chronic Oxaliplatin-Induced Neuropathy Mice Model

“…α9α10 nAChR has been proven to be expressed in immune cells and mediate noncanonical metabotropic pathways that regulate the expression of pro-inflammatory cytokine IL-β [31]. Tsetlin et al reported that α9α10 nAChR antagonists enhanced the expression of the anti-inflammatory cytokine IL-10 on mouse bone marrow granulocytes upon LPS stimulation [32]. AlSharari et al reported that the α9α10 nAChR antagonist RgIA was effective in an experimental colitis mice model and reduced the increased level of TNF-α, suggesting α9α10 nAChR as a potential target for inflammatory disorders [33].…”

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

“…RgIA4 directly and positively modulated the release of the pro-inflammatory cytokine, IL-1β, in a monocytic cell line [ 31 ]. In contrast, RgIA also increased cellular release of the potent anti-inflammatory cytokine, IL-10, from isolated granulocytes, increased their cell adhesiveness, and reduced reactive oxygen species in these cells [ 52 ]. Despite opposing effects in different cell types, the net in vivo effects of RgIA and RgIA4 are anti-inflammatory and analgesic, providing long-lasting relief and neuronal protection.…”

Conus regius-Derived Conotoxins: Novel Therapeutic Opportunities from a Marine Organism

“…The high affinity block of rα9α10 nAChRs by RgIA has been attributed, in part, to residues Asp5, Pro6; Arg7 in loop I and Arg9 in loop II [31]. The α9α10 nAChR subtype, which is critical for mediating synaptic transmission from the medial olivocochlear to the cochlear hair cells, has also been implicated in a series of pathological conditions, including neuropathic pain [26,[32][33][34][35][36], tumor proliferation [37][38][39], and immune-mediated disorders [40][41][42][43][44]. Considering the high affinity of RgIA towards this receptor subtype [11,45], its discovery led to the possibility of studying the role of α9α10 nAChRs in several diseases.…”

“…RgIA4 (see below for its amino acid composition), a RgIA derivative that lacks GABA B R activity, maintains the capacity to prevent the development of neuropathic pain [36,65,66]. Moreover, RgIA, which induces calcium transients in murine granulocytes, decreased reactive oxygen species production [42,44] and increased the production of the anti-inflammatory interleukin-10 in these cells. Even in this case, the α9α10 nAChR mechanism is more suitable than the GABA B R mechanism for explaining such regulation, given that the inhibition of VGCC currents mediated by GABA B R might result in lowering intracellular calcium, not in its increase [42].…”