Number and Locations of Agonist Binding Sites Required to Activate Homomeric Cys-Loop Receptors

Rayes, Diego; Rosa, Maria Jose de; Sine, Steven M.; Bouzat, Cecilia

doi:10.1523/jneurosci.0627-09.2009

Cited by 108 publications

(160 citation statements)

References 61 publications

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“…Results from the homomeric ␣7 nAChRs show that occupancy of two binding interfaces are required for channels to respond efficiently to ACh, although occupancy of three interfaces are required for channels to respond with maximal efficacy (39). In accordance with this, ACh activation of ␣4␤2 receptors via the two ␣4-␤2 sites and the ␣4-␣4 site leads to greater current levels than activation via the ␣4-␤2 sites alone (20).…”

Section: Discussionmentioning

confidence: 79%

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Structural and Functional Studies of the Modulator NS9283 Reveal Agonist-like Mechanism of Action at α4β2 Nicotinic Acetylcholine Receptors

Olsen

Ahring

Kastrup

et al. 2014

Journal of Biological Chemistry

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Background: Cys loop receptors can be modulated by exogenous compounds. Results: By combining x-ray crystallography, homology modeling, quantum mechanical calculations, and functional studies on ␣4␤2 nAChRs, the binding mode and modulatory mechanism of the ␣4␤2 nAChR modulator NS9283 were revealed. Conclusion: Modulatory actions occur by mimicking agonists in the ␣4-␣4 ACh-binding pocket. Significance: Increased understanding of modulator actions open new possibilities for rational drug design.

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Section: Discussionmentioning

confidence: 79%

“…However, interactions between lone pairs and centroids of aromatic rings have been confirmed to be favorable by quantum mechanical calculations and have been observed in several x-ray structures (38,39).…”

Section: Discussionmentioning

confidence: 86%

Structural and Functional Studies of the Modulator NS9283 Reveal Agonist-like Mechanism of Action at α4β2 Nicotinic Acetylcholine Receptors

Olsen

Ahring

Kastrup

et al. 2014

Journal of Biological Chemistry

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“…Combined with results obtained on homomeric receptors (Rayes et al, 2009), it seems to be a general mechanistic feature of the nAChRs that agonist binding to three sites results in maximal activation. This may also apply to other Cys-loop receptors, e.g., the GABA A receptors in which the accessory ␥-subunit adds additional plasticity to the channel activation through the benzodiazepine binding site (Atack, 2005) and thus functions similarly to the third ␣ subunit in the nAChRs.…”

Section: Fitting the Concentration-response Datamentioning

confidence: 71%

Unraveling the High- and Low-Sensitivity Agonist Responses of Nicotinic Acetylcholine Receptors

Harpsøe¹,

Ahring²,

Christensen³

et al. 2011

Journal of Neuroscience

127

240

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The neuronal ␣4␤2 nicotinic acetylcholine receptors exist as two distinct subtypes, (␣4) 2 (␤2) 3 and (␣4) 3 (␤2) 2 , and biphasic responses to acetylcholine and other agonists have been ascribed previously to coexistence of these two receptor subtypes. We offer a novel and radical explanation for the observation of two distinct agonist sensitivities. Using different expression ratios of mammalian ␣4 and ␤2 subunits and concatenated constructs, we demonstrate that a biphasic response is an intrinsic functional property of the (␣4) 3 (␤2) 2 receptor. In addition to two high-sensitivity sites at ␣4␤2 interfaces, the (␣4) 3 (␤2) 2 receptor contains a third low-sensitivity agonist binding site in the ␣4␣4 interface. Occupation of this site is required for full activation and is responsible for the widened dynamic response range of this receptor subtype. By site-directed mutagenesis, we show that three residues, which differ between the ␣4␤2 and ␣4␣4 sites, control agonist sensitivity. The results presented here provide a basic insight into the function of pentameric ligand-gated ion channels, which enables modulation of the receptors with hitherto unseen precision; it becomes possible to rationally design therapeutics targeting subpopulations of specific receptor subtypes.

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“…For the majority of Cys-loop receptors, at least two binding sites are required for channel activation, and at muscle nAChRs, the principal subunits at both these sites are the a1 subtype ; for some neuronal receptors, it appears that the two principal subunits differ within a single receptor, for instance a4 and a6 (Champtiaux et al 2003 ;Rayes et al 2009). Questions about cooperative binding are often finessed with the statement that the open state of the channel is more likely to be associated with the presence of at least two bound agonists, although certain mutant receptors have Hill slopes near unity, allowing for the possibility of opening with just a single bound agonist.…”

Section: The Ligand-binding Sitementioning

confidence: 99%

The structural basis of function in Cys-loop receptors

Thompson

Lester

Lummis

2010

Quart. Rev. Biophys.

311

388

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Abstract. Cys-loop receptors are membrane-spanning neurotransmitter-gated ion channels that are responsible for fast excitatory and inhibitory transmission in the peripheral and central nervous systems. The best studied members of the Cys-loop family are nACh, 5-HT 3 , GABA A and glycine receptors. All these receptors share a common structure of five subunits, pseudo-symmetrically arranged to form a rosette with a central ion-conducting pore. Some are cation selective (e.g. nACh and 5-HT 3 ) and some are anion selective (e.g. GABA A and glycine). Each receptor has an extracellular domain (ECD) that contains the ligand-binding sites, a transmembrane domain (TMD) that allows ions to pass across the membrane, and an intracellular domain (ICD) that plays a role in channel conductance and receptor modulation. Cys-loop receptors are the targets for many currently used clinically relevant drugs (e.g. benzodiazepines and anaesthetics). Understanding the molecular mechanisms of these receptors could therefore provide the catalyst for further development in this field, as well as promoting the development of experimental techniques for other areas of neuroscience.In this review, we present our current understanding of Cys-loop receptor structure and function. The ECD has been extensively studied. Research in this area has been stimulated in recent years by the publication of high-resolution structures of nACh receptors and related proteins, which have permitted the creation of many Cys loop receptor homology models of this region. Here, using the 5-HT 3 receptor as a typical member of the family, we describe how homology modelling and ligand docking can provide useful but not definitive information about ligand interactions. We briefly consider some of the many Cys-loop receptors modulators. We discuss the current understanding of the structure of the TMD, and how this links to the ECD to allow channel gating, and consider the roles of the ICD, whose structure is poorly understood. We also describe some of the current methods that are beginning to reveal the differences between different receptor states, and may ultimately show structural details of transitions between them.

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Number and Locations of Agonist Binding Sites Required to Activate Homomeric Cys-Loop Receptors

Cited by 108 publications

References 61 publications

Structural and Functional Studies of the Modulator NS9283 Reveal Agonist-like Mechanism of Action at α4β2 Nicotinic Acetylcholine Receptors

Structural and Functional Studies of the Modulator NS9283 Reveal Agonist-like Mechanism of Action at α4β2 Nicotinic Acetylcholine Receptors

Unraveling the High- and Low-Sensitivity Agonist Responses of Nicotinic Acetylcholine Receptors

The structural basis of function in Cys-loop receptors

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