Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor

Cooper, Ellis; Couturier, Sabine; Ballivet, Marc

doi:10.1038/350235a0

Cited by 440 publications

(261 citation statements)

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“…Within a single cholinoceptive neuron population, the different subunits segregate to assemble into two discrete classes of nAChRs that differ in subunit composition, functional properties, and spatial distribution. One class of neuronal nAChRs is a pentamer that has the general composition of two ␣ (ligand-binding) and three ␤ subunits (Anand et al, 1991;Cooper et al, 1991). The second class of neuronal nAChRs is distinguished pharmacologically by sensitivity to ␣-bungarotoxin (␣-bgt), is composed of distinct ␣-type subunits, and functions largely as homopentamers (Vernallis et al, 1993;Chen and Patrick, 1997;Drisdel and Green, 2000).…”

Section: Diversity Of Nachr Subtypesmentioning

confidence: 99%

Regulatory mechanisms that govern nicotinic synapse formation in neurons

et al. 2002

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Individual cholinoceptive neurons express high levels of different neuronal nicotinic acetylcholine receptor (nAChR) subtypes, and target them to the appropriate synaptic regions for proper function. This review focuses on the intercellular and intracellular processes that regulate nAChR expression in vertebrate peripheral nervous system (PNS) and central nervous system (CNS) neurons. Specifically, we discuss the cellular and molecular mechanisms that govern the induction and maintenance of nAChR expression-innervation, target tissue interactions, soluble factors, and activity. We define the regulatory principles of interneuronal nicotinic synapse differentiation that have emerged from these studies. We also discuss the molecular players that target nAChRs to the surface membrane and the interneuronal synapse.

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Section: Diversity Of Nachr Subtypesmentioning

confidence: 99%

Regulatory mechanisms that govern nicotinic synapse formation in neurons

et al. 2002

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“…A typical neuronal a subunit (a2, a3 or a4) will form functional nAChRs when expressed heterologously together with a typical b subunit (b2 or b4; Lindstrom, 2000). These pentameric complexes contain two copies of the a and three copies of the b subunit (Cooper et al, 1991;Boorman et al, 2000). A few a subunits (a7, a8 and a9) can form functional homomeric nAChRs when expressed alone in Xenopus oocytes.…”

Section: Introductionmentioning

confidence: 99%

Formation of functional α3β4α5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach

Groot-Kormelink

Boorman

Sivilotti

2001

British J Pharmacology

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1 The a5 subunit participates to the formation of native neuronal nicotinic receptors, particularly in autonomic ganglia. Like the related b3 subunit, a5 forms functional recombinant receptors if expressed together with a pair of typical a and b subunits, but its e ect on the properties of the resulting aba5 receptor depends on the a and b subunits chosen and on the expression system. We used a reporter mutation approach to test whether a5, like b3, is incorporated as a single copy in human a3b4a5 receptors expressed in oocytes. 2 As previously reported, the main indication of the presence of a5 in a3b4a5 wt was an increase in apparent receptor desensitization (compared with a3b4 receptors). If the a3b4a5 receptor bore a 9'T mutation in the second transmembrane domain of either a3 or b4, a5 incorporation produced a decrease in ACh sensitivity (by 4 fold for a3 LT b4a5 vs a3 LT b4 and by 40 fold for a3b4 LT a5 vs a3b4 LT ). The much greater e ect observed in a3b4 LT a5 receptors accords with the hypothesis that a5 takes the place of a b subunit in the receptor. 3 Introducing a 9'T mutation in a5 had no e ect on the agonist sensitivity of a3b4a5 receptors, but reduced apparent desensitisation, as judged by the sag in the current response to high agonist concentrations. 4 Introducing the 9'T mutation in a3 or b4 in the triplet receptor reduced the EC 50 for ACh by a similar extent (7 and 9 fold, respectively), suggesting that a3b4a5 receptors contain two copies each of a and b and therefore only one copy of a5.

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“…These unwanted effects might be minimized, or eliminated, if agents with greater selectivity are developed. .Neuronal nAChRs are pentameric complexes that closely resemble the nAChR found at the neuromuscular junction, [28,29]. Consequently, the presence of nine nAChR subunit genes (α2-α7, β2-β4) in mammalian brain (see [30] for a recent review) suggests that many, perhaps hundreds, of nAChR subtypes might be expressed in brain.…”

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confidence: 99%

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Grady

Salminen

Laverty

et al. 2007

Biochemical Pharmacology

232

223

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This review summarizes studies that attempted to determine the subtypes of nicotinic acetylcholine receptors (nAChR) expressed in the dopaminergic nerve terminals in the mouse. A variety of experimental approaches has been necessary to reach current knowledge of these subtypes, including in situ hybridization, agonist and antagonist binding, function measured by neurotransmitter release from synaptosomal preparations, and immunoprecipitation by selective antibodies. Early developments that facilitated this effort include the radioactive labeling of selective binding agents, such as [ 125 I]-α-bungarotoxin and [ 3 H]-nicotine, advances in cloning the subunits, and expression and evaluation of function of combinations of subunits in Xenopus oocytes. The discovery of epibatidine and α-conotoxin MII (α-CtxMII), and the development of nAChR subunit null mutant mice have been invaluable in determining which nAChR subunits are important for expression and function in mice, as well as allowing validation of the specificity of subunit specific antibodies. These approaches have identified five nAChR subtypes of nAChR that are expressed on dopaminergic nerve terminals. Three of these contain the α6 subunit (α4α6β2β3, α6β2β3, α6β2) and bind α-CtxMII with high affinity. One of these three subtypes (α4α6β2β3) also has the highest sensitivity to nicotine of any native nAChR that has been studied, to date. The two subtypes that do not have high affinity for α-CtxMII (α4β2, α4α5β2) are somewhat more numerous than the α6* subtypes, but do bind nicotine with high affinity. Given that our first studies detected readily measured differences in sensitivity to agonists and antagonists among these five nAChR subtypes, it seems likely that subtype selective compounds could be developed that would allow therapeutic manipulation of diverse nAChRs that have been implicated in a number of human conditions. Alterations in nicotinic cholinergic receptor (nAChRs) number or function have been implicated in psychopathologies such as anxiety, attention deficit hyperactivity disorder, depression, schizophrenia (reviewed in [1,2,3]), at least one form of familial epilepsy [4], and Parkinson's and Alzheimer's diseases [5]. It is not particularly surprising that nAChRs might play important roles in modulating several human diseases given that binding sites for nicotinic ligands such as [ 125 I]-α-bungarotoxin [6,7,8], [ 3 H]-nicotine [7,8] Corresponding author: Sharon R Grady e-mail: sharon.grady@colorado.edu phone: 303-492-9677 fax: 303-492-8063 mailing address: Institute for Behavioral Genetics University of Colorado 447UCB Boulder, CO 80309. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered w...

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Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor

Cited by 440 publications

References 22 publications

Regulatory mechanisms that govern nicotinic synapse formation in neurons

Regulatory mechanisms that govern nicotinic synapse formation in neurons

Formation of functional α3β4α5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

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