Blockade of Human α7 Nicotinic Acetylcholine Receptor by α-Conotoxin ImI Dendrimer: Insight from Computational Simulations

Abstract

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are involved in fast synaptic transmission and mediated physiological activities in the nervous system. α-Conotoxin ImI exhibits subtype-specific blockade towards homomeric α7 and α9 receptors. In this study, we established a method to build a 2×ImI-dendrimer/h (human) α7 nAChR model, and based on this model, we systematically investigated the molecular interactions between the 2×ImI-dendrimer and hα7 nAChR. Our results suggest that the 2×ImI-dendrimer possessed much stronger potency towards hα7 nAChR than the α-ImI monomer and demonstrated that the linker between α-ImI contributed to the potency of the 2×ImI-dendrimer by forming a stable hydrogen-bond network with hα7 nAChR. Overall, this study provides novel insights into the binding mechanism of α-ImI dendrimer to hα7 nAChR, and the methodology reported here opens an avenue for the design of more selective dendrimers with potential usage as drug/gene carriers, macromolecular drugs, and molecular probes.

Venom Ophthalmia and Ocular Complications Caused by Snake Venom

“…Pre-synaptic toxins (β-neurotoxins) inhibit acetylcholine (ACh) release from nerve terminals, which cause motor nerve disorders [ 73 ]. Post-synaptic toxins (α-neurotoxins) can strongly block nicotinic acetylcholine receptors (nAChR) [ 74 ], which leads to the blockade of the nerve impulse transmission [ 75 ]. Such toxic effects may cause pupillary constriction or synapse dysfunction further leading to photophobia or diplopia, respectively.…”

Inhibitory effect of sinomenine on lung cancer cells via negative regulation of α7 nicotinic acetylcholine receptor

“…Moreover, the inhibitory effects of α7 nAChR antagonists on tumor progression suggested that its receptors can be considered as a potential therapeutic target for lung cancer treatment 28 . In the NSCLC cell line H1299, Ca 2+ influx considerably increased by NIC is completely abolished by d ‐tubocurarine, and the inhibition of α‐bungarotoxin (BTX) on Ca 2+ influx decreases downstream signaling pathways, such as ERK/MAPK, and inhibits cancer cell growth 15,26,28 . SLURP‐1 (a structural homology with BTX), an allosteric modulator of α7 nAChR, can inhibit NNK‐ (a metabolite of nicotine with a 100‐fold increase in receptor affinity) stimulated oncogenic gene expression and protect the epithelium from malignant transformation that is induced by the carcinogenic compound nitrosamine 29,30 .…”

“…Its antagonists (e.g., d ‐tubocurarine or snake's neurotoxin) exert an inhibitory effect on tumors. However, the reagents used in rats cannot be used in clinical settings because of their high toxicity 12‐15 …”

“…However, the reagents used in rats cannot be used in clinical settings because of their high toxicity. [12][13][14][15] Meanwhile, 7 nAChR, as a crucial receptor of neuroimmune networks, is observed in multiple immunocytes, such as M s and lymphocytes. The cholinergic anti-inflammatory pathway (CAP) is among the manifestations in neuroimmune networks.…”

Dimerization of α-Conotoxins as a Strategy to Enhance the Inhibition of the Human α7 and α9α10 Nicotinic Acetylcholine Receptors

“…32 Recently, we showed that the substantially increased inhibitory activity of the ImI dimer at hα7 nAChR is essentially due to direct interactions of the poly(ethylene glycol) (PEG) linker with residues located between two adjacent binding sites at the extracellular domain of hα7 nAChR. 33 As α9α10 nAChR expressed from high ratio of α9 mRNA to α10 mRNA contains two neighboring α-CTxs binding sites, including the α9(+)α9(−) and α10(+)α9(−), 34 dimerization of the α-CTxs can potentially increase their binding affinity to the α9α10 nAChR. In this study, we applied the PEGdendrimerization technique to Vc1.1, RgIA# (RgIAΔR13), and PeIA in order to substantially increase their inhibitory activity at the hα7 nAChR and simultaneously enhance their potency at the hα9α10 nAChR.…”