| Structural highlights
Function
[ACHG_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHA_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHB_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHD_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [3L21A_BUNMU] Binds with high affinity to muscular (tested on Torpedo marmorata, Kd=0.4 nM) and neuronal (tested on chimeric alpha-7/CHRNA7, Kd=0.95 nM) nicotinic acetylcholine receptor (nAChR) and inhibits acetylcholine from binding to the receptor, thereby impairing neuromuscular and neuronal transmission (PubMed:9305882). It also shows an activity on GABA(A) receptors (PubMed:16549768, PubMed:25634239). It antagonises GABA-activated currents with high potency when tested on primary hippocampal neurons (PubMed:25634239). It inhibits recombinantly expressed GABA(A) receptors composed of alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits with high potency (62.3% inhibition at 20 uM of toxin) (PubMed:25634239). It also shows a weaker inhibition on GABA(A) receptors composed of alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits, alpha-4-beta-2-gamma-2 (GABRA4-GABRB2-GABRG2) subunits, and alpha-5-beta-2-gamma-2 (GABRA5-GABRB2-GABRG2) subunits (PubMed:25634239). A very weak inhibition is also observed on GABA(A) receptor composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) (PubMed:26221036). It has also been shown to bind and inhibit recombinant GABA(A) receptor beta-3/GABRB3 subunit (Kd=about 50 nM) (PubMed:16549768). In addition, it blocks the extracellular increase of dopamine evoked by nicotine only at the higher dose (4.2 uM) (PubMed:9840221).[1] [2] [3] [4]
Publication Abstract from PubMed
The nicotinic acetylcholine receptor, a pentameric ligand-gated ion channel, converts the free energy of binding of the neurotransmitter acetylcholine into opening of its central pore. Here we present the first high-resolution structure of the receptor type found in muscle-endplate membrane and in the muscle-derived electric tissues of fish. The native receptor was purified from Torpedo electric tissue and functionally reconstituted in lipids optimal for cryo-electron microscopy. The receptor was stabilized in a closed state by the binding of alpha-bungarotoxin. The structure reveals the binding of a toxin molecule at each of two subunit interfaces in a manner that would block the binding of acetylcholine. It also reveals a closed gate in the ion-conducting pore, formed by hydrophobic amino acid side chains, located approximately 60 A from the toxin binding sites. The structure provides a framework for understanding gating in ligand-gated channels and how mutations in the acetylcholine receptor cause congenital myasthenic syndromes.
Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins.,Rahman MM, Teng J, Worrell BT, Noviello CM, Lee M, Karlin A, Stowell MHB, Hibbs RE Neuron. 2020 Apr 2. pii: S0896-6273(20)30219-1. doi:, 10.1016/j.neuron.2020.03.012. PMID:32275860[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ McCann CM, Bracamontes J, Steinbach JH, Sanes JR. The cholinergic antagonist alpha-bungarotoxin also binds and blocks a subset of GABA receptors. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5149-54. doi:, 10.1073/pnas.0600847103. Epub 2006 Mar 20. PMID:16549768 doi:http://dx.doi.org/10.1073/pnas.0600847103
- ↑ Hannan S, Mortensen M, Smart TG. Snake neurotoxin alpha-bungarotoxin is an antagonist at native GABA(A) receptors. Neuropharmacology. 2015 Jun;93:28-40. doi: 10.1016/j.neuropharm.2015.01.001. Epub, 2015 Jan 26. PMID:25634239 doi:http://dx.doi.org/10.1016/j.neuropharm.2015.01.001
- ↑ Servent D, Winckler-Dietrich V, Hu HY, Kessler P, Drevet P, Bertrand D, Menez A. Only snake curaremimetic toxins with a fifth disulfide bond have high affinity for the neuronal alpha7 nicotinic receptor. J Biol Chem. 1997 Sep 26;272(39):24279-86. PMID:9305882
- ↑ Dajas-Bailador F, Costa G, Dajas F, Emmett S. Effects of alpha-erabutoxin, alpha-bungarotoxin, alpha-cobratoxin and fasciculin on the nicotine-evoked release of dopamine in the rat striatum in vivo. Neurochem Int. 1998 Oct;33(4):307-12. PMID:9840221
- ↑ Rahman MM, Teng J, Worrell BT, Noviello CM, Lee M, Karlin A, Stowell MHB, Hibbs RE. Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins. Neuron. 2020 Apr 2. pii: S0896-6273(20)30219-1. doi:, 10.1016/j.neuron.2020.03.012. PMID:32275860 doi:http://dx.doi.org/10.1016/j.neuron.2020.03.012
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