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AE Succinimide, an Analogue of Methyllycaconitine, When Bound

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AE Succinimide, an Analogue of Methyllycaconitine, When Bound pubs.acs.org/chemneuro Research Article AE Succinimide, an Analogue of Methyllycaconitine, When Bound Generates a Nonconducting Conformation of the α4β2 Nicotinic Acetylcholine Receptor Taima Qudah, Gracia X. Quek, Dinesh Indurthi, Nasiara Karim, Jill I. Halliday, Nathan Absalom, Malcolm D. McLeod, and Mary Chebib* Cite This: ACS Chem. Neurosci. 2020, 11, 344−355 Read Online ACCESS Metrics & More Article Recommendations ABSTRACT: Nicotinic acetylcholine (nACh) receptors are pentameric ligand-gated ion channels that mediate fast synaptic transmission. The α4β2 nACh receptor is highly expressed in the α β brain and exists in two functional stoichiometries: the ( 4)2( 2)3 α β ff α −α and ( 4)3( 2)2 that di er by an ACh-binding site at the 4 4 α β interface of ( 4)3( 2)2 receptors. Methyllycaconitine (MLA) is an nACh receptor antagonist, and while potent at both α7 and α4β2 nACh receptors, it has a higher selectivity for the α7 nACh receptor. The anthranilate-succinimide ester side-chain is impor- tant for its activity and selectivity. Here we identify a simplified MLA analogue that contains only the A and E ring skeleton of MLA, AE succinimide, that binds close to the channel lumen to display insurmountable inhibition at α4β2 nACh receptors. Although inhibition by AE succinimide was found to be voltage- dependent indicating a possible pore channel blocker, substituted-cysteine accessibility experiments indicated it did not bind between 2′−16′ region of the channel pore. Instead, we found that upon binding and in the presence of ACh, there is a conformational change to the channel membrane that was identified when the compound was assessed against (α4 V13′C)β2 nACh receptors. It was found that in the 3:2 stoichiometry the two adjacent α4 subunits containing 13′ cysteine mutations formed a disulfide bond and occluded ion conductance. This was reversed by treatment with the reducing agent, dithiothreitol. Thus, AE succinimide has a different mechanism of inhibition to both MLA and other AE analogues, such as AE bicyclic alcohol, in that upon binding to an as yet unidentified site, AE succinimide in the presence of ACh induces a conformational change to the channel that generates a ligand-bound closed state. KEYWORDS: Ligand-gated ion channel, nicotinic acetylcholine receptor, noncompetitive antagonist, substituted cysteine accessibility method, methyllycaconitine Downloaded via AUSTRALIAN NATL UNIV on March 16, 2020 at 22:29:16 (UTC). ■ INTRODUCTION receptor.3,4 Binding of ACh to nACh receptors at the interface See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Neuronal nicotinic acetylcholine (nACh) receptors are ligand- of two subunits in the extracellular domain results in a series of gated ion channels (LGIC) that mediate fast synaptic conformational changes that lead to the rotation of the TM2 transmission between nerve cells. These receptors are widely domain to open the channel. ff α −α distributed in both the peripheral and central nervous systems To date, 12 di erent nACh receptor subunits ( 2 10 and β −β fi and have been implicated in different physiological and 2 4) have been identi ed and cloned from the mammalian neurological conditions including Alzheimer’s disease, nicotine brain. Different arrangements of these subunits lead to a wide addiction, pain, epilepsy, and schizophrenia.1,2 variety of individual receptor subtypes, each with distinct Nicotinic acetylcholine receptors are assembled from five pharmacological and physiological properties.1,2 Therefore, subunits that are arranged pseudosymmetrically around a there is great interest in developing selective neuronal nACh central cation-conducting pore. Each subunit is composed of a receptor ligands as research tools and therapeutic agents in large extracellular N-terminal region, four transmembrane − domains (TM1 TM4), two short loops between TM1 and Received: September 29, 2019 TM2 and between TM2 and TM3, a large intracellular loop Accepted: January 3, 2020 between TM3 and TM4, and a short extracellular carboxy Published: January 3, 2020 terminal. The channel pore is lined by the α-helical TM2 domain, where cations passively pass through the open © 2020 American Chemical Society https://dx.doi.org/10.1021/acschemneuro.9b00525 344 ACS Chem. Neurosci. 2020, 11, 344−355 ACS Chemical Neuroscience pubs.acs.org/chemneuro Research Article order to understand the role each receptor subtype plays in receptors, it is selective for α7 nACh receptors (picomolar brain function. versus nanomolar affinity, respectively).15,16 Despite this The TM2 domain incorporates the binding site for many difference in potency, we pursued developing a series of noncompetitive antagonists, including tetracaine, carbamaze- simpler MLA analogues that had the A and E ring skeleton of pine,andbarbiturates,aswellasanestheticssuchas MLA, including AE succinimide and AE bicyclic alcohol phencylidine and ketamine (for a review, see ref 5). Many (Figure 1), that incorporated either the anthranilate- noncompetitive antagonists inhibit nACh receptors by binding succinimide (2-[3-methyl-2,5-dioxopyrrolidin-1-yl]benzoate) within the channel lumen, occluding it and physically blocking or alcohol side-chains,17,18 respectively, in order to identify ion permeability. Some channel blockers such as quinacrine compounds that were more potent for α4β2 nACh receptors. appear to bind only when the channel pore opens, requiring an Structure−activity studies on MLA analogues had previously agonist such as ACh to first bind at orthosteric sites to demonstrated that the anthranilate-succinimide moiety is a key modulate the accessibility of channel blockers to the pore.6 structural determinant for competitive receptor binding at α7 Other noncompetitive antagonists block both the open and receptors, possibly anchoring the compound to the orthosteric- closed states of the receptor.5,7,8 binding site. However, at α4β2 nACh receptors, both MLA Of the many reported receptor subtypes, the homomeric α7 and anthranilate-succinimide analogues displayed either and heteromeric α4β2 nACh receptors are the most widely competitive or insurmountable inhibition depending on expressed in the brain.1 The α4β2 nACh receptor exists in two whether the antagonist was preincubated or not.18 In contrast, pharmacologically distinct receptor stoichiometries, analogues of MLA that lacked the anthranilate-succinimide α β α β α β ( 4)2( 2)3 and ( 4)3( 2)2. The ( 4)2( 2)3 nACh receptor side chain, such as AE bicyclic alcohol, bound solely to the α β ′ 18,19 α β has high sensitivity to ACh, whereas the ( 4)3( 2)2 nACh TM2 domain at the 13 position of 4 2 nACh receptors receptor has lower sensitivity. The difference in sensitivities to as a noncompetitive channel blocker. ACh between the two stoichiometries is due to the presence of In the work presented here, we determined that in contrast a third low-affinity ACh-binding site located at the α4−α4 to AE bicyclic alcohol, AE succinimide does not directly bind α β ′ interface in the ( 4)3( 2)2 stoichiometry, and this site is in to the 13 site of the TM2 domain but binds to several sites addition to the two common α4−β2 binding sites that occur in including the orthosteric site and a site close to or within the − both stoichiometries.9 14 channel lumen to inhibit α4β2 nACh receptors. By mutating Methyllycaconitine (MLA) (Figure 1) is an nACh receptor the 13′ site of the α4 subunit TM2 domain to a cysteine, we antagonist, and while potent at both α7 and α4β2 nACh show that AE succinimide in the presence of ACh induces a conformational change in the α4 subunit that enables adjacent cysteines within the channel pore to form a disulfide bond occluding ion conductance. This can be reversed with DTT. Thus, AE succinimide has a different mechanism of inhibition to both MLA and AE bicyclic alcohol α4β2 nACh receptor. ■ RESULTS AND DISCUSSION AE Succinimide Incubation Dictates Surmountable and Insurmountable Inhibition of ACh at α4β2 Receptors. In this study we evaluated the effect of AE succinimide against rat α4β2 nACh receptor stoichiometries. The assembly of different stoichiometries of α4β2 nACh receptors in Xenopus laevis oocytes can be directed by injecting oocytes with different ratios of α4toβ2 mRNA. Acetylcholine differs in potency at each receptor because it can bind to two Figure 1. Chemical structures for methyllycaconitine (MLA), AE distinct interfaces within the extracellular domain; the α4−β2 succinimide, and AE bicyclic alcohol. and α4−α4 interfaces. Thus, to express the two stoichiome- tries, we used an excess amount of β2 subunit mRNA in either Table 1. Pharmacological Data for ACh Alone and in the Presence of AE Succinimide with and without a 3 min Preincubation at α4β2 (1:10) and α4β2 (1:1) nACh Receptors incubation μ b c,h d c,i e c receptor ratio application (min) EC50 ( M) (95% CI) IMax (95% CI) nH (95% CI) n α4β2 (1:10)a ACh alone none 1.7 (1.2−2.4) 1.04 (0.98−1.11) 0.88 (0.6−1.2) 4 α4β2 (1:1) ACh alone none 136 (99.5−186.5) 1.16 (1.06−1.26) 0.98 (0.72−1.23) 11 α4β2 (1:1) ACh + 30 μM AE succinimide none 2.6 (0.13−52.2)912 (506−1644)*** 1.07 (0.96−1.17) n.d.g 6 α4β2 (1:1) ACh + 3 μM AE succinimide 3 446 (291.1−683.7)*** 0.97 (0.90− 1.17) 1.09 (0.90−1.51) 5 α4β2 (1:1) ACh + 30 μM AE succinimidef 3 561 (149.1−2105)*** 0.5 (0.30−0.70)** 0.92 (−0.09 to 1.90) 5 a b ff c fi d Data taken from ref 20. EC50 is the e ective concentration that activates 50% of the receptor. 95% con dence intervals (CI). IMax is the e ffi f maximum current produced by ACh alone or ACh in the presence of an antagonist.
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