A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip

Gupta, Shaweta; Chakraborty, Srirupa; Vij, Ridhima; Auerbach, Anthony

doi:10.1085/jgp.201611673

Cited by 56 publications

(94 citation statements)

References 88 publications

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“…Regardless of whether a new proton sensor is created or proton sensitivity of an existing site is altered, the biphasic proton dose response curves stem from mismatched interactions between the GLIC ECD and GABAρ TMD. These data provide support for the idea that agonist-mediated pLGIC gating transitions are regulated by specific interdomain interactions between the ECD and TMD (Bertozzi et al, 2016; Gupta et al, 2017; Lee and Sine, 2005; Xiu et al, 2005). …”

Section: Discussionsupporting

confidence: 70%

“…At the ECD-TMD interface, connections between flexible loops in the extracellular binding domain (loops 2, 7, 9) with the transmembrane channel domain (M2–M3 loop) structurally link the two domains and are essential for coupling ligand binding to channel gating (Miller and Smart, 2010). Agonist-mediated closed to open channel gating transitions are accompanied by substantial rearrangements of this interface (Bertozzi et al, 2016; Dellisanti et al, 2013; Gupta et al, 2017; Lee and Sine, 2005; Velisetty et al, 2014; Xiu et al, 2005). In chimeric channels assembled by combining the ECD and TMD of two distinct pLGICs, substantial loop substitutions are required to maintain complementarity and ensure normal channel function (Bouzat et al, 2008; Bouzat et al, 2004; Eisele et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation

2017

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Pentameric ligand-gated ion channels (pLGICs) are the targets of several clinical and endogenous allosteric modulators including anesthetics and neurosteroids. Molecular mechanisms underlying allosteric drug modulation are poorly understood. Here, we constructed a chimeric pLGIC by fusing the extracellular domain (ECD) of the proton-activated, cation-selective bacterial channel GLIC to the transmembrane domain (TMD) of the human ρ1 chloride-selective GABAAR, and tested the hypothesis that drug actions are regulated locally in the domain that houses its binding site. The chimeric channels were proton-gated and chloride-selective demonstrating the GLIC ECD was functionally coupled to the GABAρ TMD. Channels were blocked by picrotoxin and inhibited by pentobarbital, etomidate and propofol. The point mutation, ρ TMD W328M, conferred positive modulation and direct gating by pentobarbital. The data suggest that the structural machinery mediating general anesthetic modulation resides in the TMD. Proton-activation and neurosteroid modulation of the GLIC-ρ chimeric channels, however, did not simply mimic their respective actions on GLIC and GABAρ revealing that across domain interactions between the ECD and TMD play important roles in determining their actions. Proton-induced current responses were biphasic suggesting that the chimeric channels contain an additional proton sensor. Neurosteroid modulation of the GLIC-ρ chimeric channels by the stereoisomers, 5α-THDOC and 5β-THDOC, were swapped compared to their actions on GABAρ indicating that positive versus negative neurosteroid modulation is not encoded solely in the TMD nor by neurosteroid isomer structure but is dependent on specific interdomain connections between the ECD and TMD. Our data reveal a new mechanism for shaping neurosteroid modulation.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation

2017

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“…As illustrated in Figure a, the interface between the ECD and TMD comprises a linker between the ECD β10 strand and the M1 α‐helix of the TMD, as well as three loops named β1–β2 linker, M2–M3 linker, and the Cys‐loop. A strong energy coupling was observed between the central part of the M2–M3 linker and the β1–β2 linker (P271; Gupta, Chakraborty, Vij, & Auerbach, ), and we used the distance between the central residues of these linkers, which we call the “activation distance,” to characterise different activation states (Table S2). The experimental structures of the glycine receptor, GLIC, and GluCl captured in various activation states provide evidence that the closed/resting state displays an activation distance that is longer than that of the open or desensitised states (6–8 Å compared to 4–5 Å).…”

Section: Resultsmentioning

confidence: 99%

Molecular dynamics simulations of dihydro‐β‐erythroidine bound to the human α4β2 nicotinic acetylcholine receptor

Tae

et al. 2019

British J Pharmacology

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Background and Purpose: The heteromeric α4β2 nicotinic acetylcholine receptor (nAChR) is abundant in the human brain and is associated with a range of CNS disorders. This nAChR subtype has been recently crystallised in a conformation that was proposed to represent a desensitised state. Here, we investigated the conformational transition mechanism of this nAChR from a desensitised to a closed/resting state.Experimental Approach: The competitive antagonist dihydro-β-erythroidine (DHβE) was modelled by replacement of the agonist nicotine in the α4β2 nAChR experimental structure. DHβE is used both in vitro and in vivo for its ability to block α4β2 nAChRs. This system was studied by three molecular dynamics simulations with a combined simulation time of 2.6 μs. Electrophysiological studies of mutated receptors were performed to validate the simulation results. Key Results: The relative positions of the extracellular and transmembrane domains in the models are distinct from those of the desensitised state structure and are compatible with experimental structures of Cys-loop receptors captured in a closed/resting state.Conclusions and Implications: Our model suggests that the side chains of α4 L257 (9′) and α4 L264 (16′) are the main constrictions in the transmembrane pore. The involvement of position 9′ in channel gating is well established, but position 16′ was only previously identified as a gate for the bacterial channels, ELIC and GLIC. L257 but not L264 was found to influence the slow component of desensitisation.The structure of the antagonist-bound state proposed here should be valuable for the development of therapeutic or insecticide compounds.

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“…The set of characters, or morphological features, that a particular biological structure exhibits is related to its function, as broadly exemplified across the gamut of morphology -from the biomechanics of jaws [Nishikawa and Gans, 1996] to amino acid components of nicotinic acetylcholinergic receptors [Gupta et al, 2017] to the cytoarchitecture of visual cortex [Hubel and Wiesel, 1968]. However, such observations need to be tempered with the recognition that particular functions may involve different hierarchical levels of structure, such as whether the electrical activity in a muscle is based on the neural innervation of the muscle or the membrane properties and sodium channels of the cells involved [Lauder, 1994].…”

mentioning

confidence: 99%

Of Horse-Caterpillars and Homologies: Evolution of the Hippocampus and Its Name

Butler

2017

Brain Behav Evol

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The hippocampus was first named in mammals based on the appearance of its gross morphological features, one end of it being fancied to resemble the head of a horse and the rest of it a silkworm, or caterpillar. A hippocampus, occupying the most medial part of the telencephalic pallium, has subsequently been identified in diverse nonmammalian taxa, but in which the “horse-caterpillar” morphology is lacking. While some strikingly similar functional similarities have been identified, questions of its homology (“sameness”) across these taxa and about the very fundamental relationship of structure to function in central nervous system structures remain open. The hippocampal formation of amniotes participates in allocentric (external landmark) spatial navigation, memory, and attention to novel stimuli, and these functions generally are shared across amniotes despite variation in its morphological features. Substantially greater deviation in its morphology occurs in anamniotes, including amphibians and ray-finned fishes (actinopterygians), but its functions of allocentric spatial navigation and/or memory have been found to be preserved by studies in these taxa. Its shared functional roles cannot be used as evidence of structural homology, but given that other criteria indicate homology of the medial pallial derivative across these clades, the similar functions themselves may be regarded as homologous functions if they are based on the same cellular mechanisms and connections. The question arises as to whether the similar functions are performed by as yet undiscovered, shared morphological features or by different features that accomplish the same results via different mechanisms of neural function.

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A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip

Cited by 56 publications

References 88 publications

A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation

A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation

Molecular dynamics simulations of dihydro‐β‐erythroidine bound to the human α4β2 nicotinic acetylcholine receptor

Of Horse-Caterpillars and Homologies: Evolution of the Hippocampus and Its Name

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