Gating of nicotinic ACh receptors: Latest insights into ligand binding and function

Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Department of Health and Human Services, PO Box 12233, Research Triangle Park, NC 27709, USA.
The Journal of Physiology (Impact Factor: 4.54). 11/2009; 588(Pt 4):597-602. DOI: 10.1113/jphysiol.2009.182691
Source: PubMed

ABSTRACT Nicotinic acetylcholine receptors (nAChRs) are in the superfamily of cys-loop receptors, and are widely expressed in the nervous system where they participate in a variety of physiological functions, including regulating excitability and neurotransmitter release, as well as neuromuscular contraction. Members of the cys-loop family of receptors, which also includes the molluscan ACh-binding protein (AChBP), a soluble protein that is analogous to the extracellular ligand-binding domain of the cys-loop receptors, are pentameric assemblies of five subunits, with each subunit arranged around a central pore. The binding of ACh to the extracellular interface between two subunits induces channel opening. With the recent 4 A resolution of the Torpedo nAChR, and the crystal structure of the AChBP, much has been learned about the structure of the ligand-binding domain and the channel pore, as well as major structural rearrangements that may confer channel opening, including a major rearrangement of the C-loop within the ligand binding pocket, and perhaps other regions including the F-loop (the beta8-beta9 linker), the beta1-beta2 linker and the cys-loop. Here I will review the latest findings from my lab aimed at a further understanding of the function of the neuronal nAChR channels (and in particular the role of desensitization), and our search for novel AChBP species that may lead to a further understanding of the function of the cys-loop receptor family.

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    • "Only 5 subunit does not binds ligand since one tyrosine residue is missing [12]. The nAChR sub-types may comprise binary (homomeric including the phylogenetically ancient 7 subunits, or heteromeric nAChR such as 42), ternary (such as 425) or quaternary (such as 3245) complexes [13]. When activated by acetylcholine , or other agonists such as nicotine, the nAChR allow intracellular influx of Ca 2+ determining several effects on pathways regulating cell proliferation, survival and motility [reviewed in 14]. "
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    ABSTRACT: Cigarette smoking is one of the major risk factors for COPD and COPD severity. In turn COPD is a major independent risk factor for lung cancer. Genome-wide association (GWA) studies both in lung cancer and COPD highlighted the same variants (SNPs) on chromosome 15q25 marking the gene cluster CHRNA3-CHRNB4-CHRNA5 for these smoking related diseases, showing a stimulating connection between this common genetic region and smoking behavior and smoking related illnesses. Different authors identified two candidate regions associated with age at smoking initiation in patients with COPD. The nicotinic acetylcholine receptor polymorphism (rs1051730) on chromosome 15q25 is associated with major tobacco-related diseases in the general population with additional increased risk of COPD as well as lung cancer. Moreover variants on the gene cluster CHRNA3-CHRNB4-CHRNA5 are associated with nicotine addiction antismoking therapy and antismoking therapy side-effects. These findings not only support the notion that variants can influence any therapy for smoking cessation, but offer rational bases to develop new drugs and new therapeutic strategies.
    Current Medicinal Chemistry 10/2012; DOI:10.2174/092986712804143312 · 3.85 Impact Factor
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    • "Nicotinic acetylcholine receptors (nAChRs) belong to the cys-loop superfamily of ligand-gated ion channels (LGICs), which form pentamers of homologous subunits organized around a central pore (Corringer et al. 2000; Giniatullin et al. 2005; Unwin, 2005; Sine & Engel, 2006; Gay & Yakel, 2007; Yakel, 2010). The binding of the neurotransmitter ACh to the extracellular interface between two nAChR subunits brings about a structural change which leads to channel opening. "
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    ABSTRACT: The rat α7 nicotinic acetylcholine receptor (nAChR) has a proline residue near the middle of the β9 strand. The replacement of this proline residue at position 180 (P180) by either threonine (α7-P180T) or serine (α7-P180S) slowed the onset of desensitization dramatically, with half-times of ~930 and 700 ms, respectively, compared to 90 ms for the wild-type receptor. To investigate the importance of the hydroxyl group on the position 180 side-chains, the mutant receptors α7-P180Y and α7-P180F were studied and showed half-times of desensitization of 650 and 160 ms, respectively. While a position 180 side-chain OH group may contribute to the slow desensitization rates, α7-P180S and α7-P180V resulted in receptors with similar desensitization rates, suggesting that increased backbone to backbone H bonding expected in the absence of proline at position 180 would likely exert a great effect on desensitization. Single channel recordings indicated that for the α7-P180T receptor there was a significantly reduced closed time without any change in single channel conductance (as compared to wild-type). Kinetic simulations indicated that all changes observed for the mutant channel behaviour were reproduced by decreasing the rate of desensitization, and increasing the microscopic affinity to resting receptors. Molecular dynamics (MD) simulations on a homology model were used to provide insight into likely H bond interactions within the outer β-sheet that occur when the P180 residue is mutated. All mutations analysed increased about twofold the predicted number of H bonds between the residue at position 180 and the backbone of the β10 strand. Moreover, the α7-P180T and α7-P180S mutations also formed some intrastrand H bonds along the β9 strand, although H bonding of the OH groups of the threonine or serine side-chains was predicted to be infrequent. Our results indicate that rapid desensitization of the wild-type rat α7 nAChR is facilitated by the presence of the proline residue within the β9 strand.
    The Journal of Physiology 11/2010; 588(Pt 22):4415-29. DOI:10.1113/jphysiol.2010.195495 · 4.54 Impact Factor
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    • "-channel conductance (y16 pS in 5-HT 3 AB compared to <1 pS in 5-HT 3 A ; Davies et al. 1999 ; Dubin et al. 1999). However, the pharmacology of 5-HT 3 A and 5-HT 3 AB receptors is almost identical, suggesting that they contain a common binding site (an A–A interface), a hypothesis supported by a recent study of mouse 5-HT 3 AB receptors (Brady et al. 2001 ; Lochner & Lummis, 2010), but conflicting with the BABBA arrangement determined using atomic force microscopy (Barrera et al. 2005). The subunit types and stoichiometry of 5-HT 3 Rs have been recently reviewed (Barnes et al. 2009 ; Jensen et al. 2008)."
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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-HT3, GABAA 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-HT3) and some are anion selective (e.g. GABAA 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-HT3 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.
    Quarterly Reviews of Biophysics 11/2010; 43(4):449-99. DOI:10.1017/S0033583510000168 · 10.08 Impact Factor
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