Progress in nicotinic receptor structural biology

Gharpure, Anant; Noviello, Colleen; Hibbs, Ryan

doi:10.1016/j.neuropharm.2020.108086

Cited by 75 publications

(61 citation statements)

References 189 publications

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“…12 They are present in both the peripheral (at the skeletal neuromuscular junction and in the autonomic nervous system) and central nervous system (CNS). 13 The neuronal receptors have emerged as important targets for the treatment of Alzheimer's disease, schizophrenia, pain and nicotine addiction. 13,14 Mutations of muscle nAChR can cause congenital myasthenia gravis.…”

Section: Main Textmentioning

confidence: 99%

“…13 The neuronal receptors have emerged as important targets for the treatment of Alzheimer's disease, schizophrenia, pain and nicotine addiction. 13,14 Mutations of muscle nAChR can cause congenital myasthenia gravis. 4 There is a large repertoire of nAChR subtypes which differ in the homo-or heteromeric assembly of five monomers arranged around a central channel axis.…”

Section: Main Textmentioning

confidence: 99%

See 1 more Smart Citation

Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors

Oliveira

Ibarra

Bermúdez

et al. 2020

Preprint

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Changeux et al. recently suggested that the SARS-CoV-2 spike (S) protein may interact with nicotinic acetylcholine receptors (nAChRs). Such interactions may be involved in pathology and infectivity. Here, we use molecular simulations of validated atomically detailed structures of nAChRs, and of the S protein, to investigate this "nicotinic hypothesis". We examine the binding of the Y674-R685 loop of the S protein to three nAChRs, namely the human α4β2 and α7 subtypes and the muscle-like αβγδ receptor from Tetronarce californica. Our results indicate that Y674-R685 has affinity for nAChRs and the region responsible for binding contains the PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. In particular, R682 has a key role in the stabilisation of the complexes as it forms interactions with loops A, B and C in the receptors binding pocket. The conformational behaviour of the bound Y674-R685 region is highly dependent on the receptor subtype, adopting extended conformations in the α4β2 and α7 complexes and more compact ones when bound to the muscle-like receptor. In the α4β2 and αβγδ complexes, the interaction of Y674-R685 with the receptors forces the loop C region to adopt an open conformation similar to other known nAChR antagonists. In contrast, in the α7 complex, Y674-R685 penetrates deeply into the binding pocket where it forms interactions with the residues lining the aromatic box, namely with TrpB, TyrC1 and TyrC2. Estimates of binding energy suggest that Y674-R685, forms stable complexes with all three nAChR subtypes, but has highest affinity for the muscle-type receptor. Analyses of the simulations of the full-length S protein show that the Y674-R685 region is accessible for binding, and suggest a potential binding orientation of the S protein with nAChRs.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors

Oliveira

Ibarra

Bermúdez

et al. 2020

Preprint

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“…Obtaining and solving structures of ion channels with or without peptide toxins has historically been challenging [ 33 ], notwithstanding some outstanding crystal (Xtal) structure exceptions [ 34 , 35 ]. This situation has changed dramatically with recent advances in cryo-electron microscopy (cryo-EM), particularly regarding sample preparation [ 36 ], that have made determination of ion channel structures that were previously difficult, such as nicotinic acetylcholine receptors (nAChRs), more facile [ 37 ]. In turn, breakthrough structures of peptide toxins with therapeutically relevant, human ion channels have begun to appear [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Water Thermodynamics of Peptide Toxin Binding Sites on Ion Channels

Shah

Sindhikara

Borrelli

et al. 2020

Toxins

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Peptide toxins isolated from venomous creatures, long prized as research tools due to their innate potency for ion channels, are emerging as drugs as well. However, it remains challenging to understand why peptide toxins bind with high potency to ion channels, to identify residues that are key for activity, and to improve their affinities via mutagenesis. We use WaterMap, a molecular dynamics simulation-based method, to gain computational insight into these three questions by calculating the locations and thermodynamic properties of water molecules in the peptide toxin binding sites of five ion channels. These include an acid-sensing ion channel, voltage-gated potassium channel, sodium channel in activated and deactivated states, transient-receptor potential channel, and a nicotinic receptor whose structures were recently determined by crystallography and cryo-electron microscopy (cryo-EM). All channels had water sites in the peptide toxin binding site, and an average of 75% of these sites were stable (low-energy), and 25% were unstable (medium or high energy). For the sodium channel, more unstable water sites were present in the deactivated state structure than the activated. Additionally, for each channel, unstable water sites coincided with the positions of peptide toxin residues that previous mutagenesis experiments had shown were important for activity. Finally, for the sodium channel in the deactivated state, unstable water sites were present in the peptide toxin binding pocket but did not overlap with the peptide toxin, suggesting that future experimental efforts could focus on targeting these sites to optimize potency.

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“…Nicotine acts on nicotinic acetylcholine receptors (nAChRs), ultimately causing an increase in dopamine release and fueling signaling cascades along the reward pathway. Studies implicate nAChRs and miRNAs in aggravating the effects of nicotine [89,127,128]. Elucidation of these specific mechanisms could advance our understanding of EVs in the development of nicotine addiction and subsequent CNS disorders.…”

Section: Nicotinementioning

confidence: 99%

Role of Extracellular Vesicles in Substance Abuse and HIV-Related Neurological Pathologies

Odegaard

Chand

Wheeler

et al. 2020

IJMS

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Extracellular vesicles (EVs) are a broad, heterogeneous class of membranous lipid-bilayer vesicles that facilitate intercellular communication throughout the body. As important carriers of various types of cargo, including proteins, lipids, DNA fragments, and a variety of small noncoding RNAs, including miRNAs, mRNAs, and siRNAs, EVs may play an important role in the development of addiction and other neurological pathologies, particularly those related to HIV. In this review, we summarize the findings of EV studies in the context of methamphetamine (METH), cocaine, nicotine, opioid, and alcohol use disorders, highlighting important EV cargoes that may contribute to addiction. Additionally, as HIV and substance abuse are often comorbid, we discuss the potential role of EVs in the intersection of substance abuse and HIV. Taken together, the studies presented in this comprehensive review shed light on the potential role of EVs in the exacerbation of substance use and HIV. As a subject of growing interest, EVs may continue to provide information about mechanisms and pathogenesis in substance use disorders and CNS pathologies, perhaps allowing for exploration into potential therapeutic options.

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Progress in nicotinic receptor structural biology

Cited by 75 publications

References 189 publications

Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors

Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors

Water Thermodynamics of Peptide Toxin Binding Sites on Ion Channels

Role of Extracellular Vesicles in Substance Abuse and HIV-Related Neurological Pathologies

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