Cys-loop receptors: new twists and turns

Lester, Henry A.; Dibas, Mohammed; Dahan, David; Leite, John F.; Dougherty, Dennis A.

doi:10.1016/j.tins.2004.04.002

Cited by 379 publications

(283 citation statements)

References 90 publications

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“…A c c e p t e d M a n u s c r i p t 8 interactions in the stabilization of the nicotinic ligand cation [36,37]. Structures of AChBP complexes with these small agonists indeed reveal that the tertiary nitrogen of nicotine and epibatidine or the quaternary nitrogen of carbamylcholine interact with the negative charge generated by the π electrons from the side chains of the residues making up the aromatic cage [23,38].…”

Section: Tools Towards Nachr Structurementioning

confidence: 99%

Insight in nAChR subtype selectivity from AChBP crystal structures

Rucktooa

Smit²,

Sixma

2009

Biochemical Pharmacology

119

118

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Nicotinic acetylcholine receptors (nAChRs) display a broad variety of subtypes, which in turn present a complex subcellular and regional expression pattern in the brain, as well as a specific pharmacological profile. The association of these nAChRs with different types of brain disease has turned them into interesting drug targets for the treatment of Alzheimer's disease or schizophrenia, or for anti-smoking compounds among others. In the same way, muscle-type nAChRs present at neuromuscular junctions are also being targeted by muscle relaxants. However, to date no high-resolution structural data is available on functional

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Section: Tools Towards Nachr Structurementioning

confidence: 99%

Insight in nAChR subtype selectivity from AChBP crystal structures

Rucktooa

Smit²,

Sixma

2009

Biochemical Pharmacology

119

118

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“…This family includes nicotinic receptors (nAChRs), serotonin receptor type 3 (5-HT 3 R), γ-aminobutyric acid receptors type A and C (GABA A/C ), glycine receptors, zinc-activated cation channel, and invertebrate glutamate/ serotonin-activated anionic channels or GABA-gated cation channels [1][2][3] . Recently, prokaryotic proton-gated ion channels are also considered to be in the same family although they are devoid of the signature cysteine loop [4] .…”

Section: Introductionmentioning

confidence: 99%

Allosteric activation mechanism of the cys-loop receptors

et al. 2009

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Binding of a neurotransmitter to its ionotropic receptor opens a distantly located ion channel, a process termed allosteric activation. Here we review recent advances in the molecular mechanism by which the cys-loop receptors are activated with emphasis on the best studied nicotinic acetylcholine receptors (nAChRs). With a combination of affinity labeling, mutagenesis, electrophysiology, kinetic modeling, electron microscopy (EM), and crystal structure analysis, the allosteric activation mechanism is emerging. Specifically, the binding domain and gating domain are interconnected by an allosteric activation network. Agonist binding induces conformational changes, resulting in the rotation of a β sheet of aminoterminal domain and outward movement of loop 2, loop F, and cys-loop, which are coupled to the M2-M3 linker to pull the channel to open. However, there are still some controversies about the movement of the channel-lining domain M2. Nine angstrom resolution EM structure of a nAChR imaged in the open state suggests that channel opening is the result of rotation of the M2 domain. In contrast, recent crystal structures of bacterial homologues of the cys-loop receptor family in apparently open state have implied an M2 tilting model with pore dilation and quaternary twist of the whole pentameric receptor. An elegant study of the nAChR using protonation scanning of M2 domain supports a similar pore dilation activation mechanism with minimal rotation of M2. This remains to be validated with other approaches including high resolution structure determination of the mammalian cys-loop receptors in the open state.

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“…allosteric potentiation | neurotransmitter receptor N icotinic acetylcholine receptors (nAChRs) are pentameric neurotransmitter-gated ion channels and are members of the superfamily of Cys-loop receptors that includes receptors for 5-hydroxytryptamine (5-HT), GABA, and glycine (1). Nicotinic receptors are, themselves, a diverse family of receptors (2,3).…”

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confidence: 99%

Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

Gill

Savolainen

Young

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

118

194

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Conventional nicotinic acetylcholine receptor (nAChR) agonists, such as acetylcholine, act at an extracellular "orthosteric" binding site located at the interface between two adjacent subunits. Here, we present evidence of potent activation of α7 nAChRs via an allosteric transmembrane site. Previous studies have identified a series of nAChR-positive allosteric modulators (PAMs) that lack agonist activity but are able to potentiate responses to orthosteric agonists, such as acetylcholine. It has been shown, for example, that TQS acts as a conventional α7 nAChR PAM. In contrast, we have found that a compound with close chemical similarity to TQS (4BP-TQS) is a potent allosteric agonist of α7 nAChRs. Whereas the α7 nAChR antagonist metyllycaconitine acts competitively with conventional nicotinic agonists, metyllycaconitine is a noncompetitive antagonist of 4BP-TQS. Mutation of an amino acid (M253L), located in a transmembrane cavity that has been proposed as being the binding site for PAMs, completely blocks agonist activation by 4BP-TQS. In contrast, this mutation had no significant effect on agonist activation by acetylcholine. Conversely, mutation of an amino acid located within the known orthosteric binding site (W148F) has a profound effect on agonist potency of acetylcholine (resulting in a shift of ∼200-fold in the acetylcholine dose-response curve), but had little effect on the agonist dose-response curve for 4BP-TQS. Computer docking studies with an α7 homology model provides evidence that both TQS and 4BP-TQS bind within an intrasubunit transmembrane cavity. Taken together, these findings provide evidence that agonist activation of nAChRs can occur via an allosteric transmembrane site.allosteric potentiation | neurotransmitter receptor

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Cys-loop receptors: new twists and turns

Cited by 379 publications

References 90 publications

Insight in nAChR subtype selectivity from AChBP crystal structures

Insight in nAChR subtype selectivity from AChBP crystal structures

Allosteric activation mechanism of the cys-loop receptors

Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

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