Neuronal Nicotinic Receptor a6 Subunit mRNA is Selectively Concentrated in Catecholaminergic Nuclei of the Rat Brain

Novère, Nicolas Le; Zoli, Michèle; Changeux, Jean Pierre

doi:10.1111/j.1460-9568.1996.tb01206.x

Cited by 352 publications

(292 citation statements)

References 59 publications

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“…The use of other ligands such as radiolabeled nicotine, α-bungarotoxin and α-conotoxinMII has helped identify nAChR subtypes, including those containing the α4, α6 and α7 subunits [67,69,71]. These findings from receptor binding studies are in agreement with the results of in situ hybridization and RT-PCR work, which demonstrate the presence of α2 through α7 and β2 through β4 nAChR subunit transcripts in the striatum and/or substantia nigra [72][73][74][75][76][77]. The results of immunoprecipitation studies using subunit-selective nAChR antibodies suggest that the greater majority of these transcripts are translated into protein to form receptors [64,78].…”

Section: Rodentssupporting

confidence: 61%

Nicotinic receptors as CNS targets for Parkinson's disease

Quik

Bordia

O’Leary

2007

Biochemical Pharmacology

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Parkinson's disease is a debilitating neurodegenerative movement disorder characterized by damage to the nigrostriatal dopaminergic system. Current therapies are symptomatic only and may be accompanied by serious side effects. There is therefore a continual search for novel compounds for the treatment of Parkinson's disease symptoms, as well as to reduce or halt disease progression. Nicotine administration has been reported to improve motor deficits that arise with nigrostriatal damage in parkinsonian animals and in Parkinson's disease. In addition, nicotine protects against nigrostriatal damage in experimental models, findings that have led to the suggestion that the reduced incidence of Parkinson's disease in smokers may be due to the nicotine in tobacco. Altogether, these observations suggest that nicotine treatment may be beneficial in Parkinson's disease. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle. Work to identify the subtypes affected in Parkinson's disease is therefore critical for the development of targeted therapies. Results show that striatal α6β2-containing nAChRs are particularly susceptible to nigrostriatal damage, with a decline in receptor levels that closely parallels losses in striatal dopamine. In contrast, α4β2-containing nAChRs are decreased to a much smaller extent under the same conditions. These observations suggest that development of nAChR agonists or antagonists targeted to α6β2-containing nAChRs may represent a particularly relevant target for Parkinson's disease therapeutics. Keywordsα-ConotoxinMII; Nicotine; Nicotinic; Parkinson's disease; Nigrostriatal; Striatum Parkinson's disease and the nicotinic cholinergic systemThe pathological hallmarks of Parkinson's disease are the presence of intracellular Lewy bodies and an extensive degeneration of the nigrostriatal dopaminergic system. [1][2][3][4]. There is a ≥70% decline in striatal dopamine and ≥50% loss of nigral dopaminergic neurons with the onset of clinical symptoms, which include bradykinesia, rigidity, and tremor [1][2][3][4].Although Parkinson's disease has primarily been considered a dopaminergic disorder, it is becoming increasingly clear that multiple CNS systems are involved in its pathogenesis [5][6][7]. Braak and coworkers have also identified Lewy bodies in numerous non-dopaminergic brain regions including the locus coeruleus, raphe nuclei, thalamus, amygdala, olfactory nuclei, pedunculopontine nucleus, and cerebral cortex [5,6]. These observations are in agreement with much earlier studies, which indicated that multiple CNS neuronal systems are affected in 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...

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Section: Rodentssupporting

confidence: 61%

Nicotinic receptors as CNS targets for Parkinson's disease

Quik

Bordia

O’Leary

2007

Biochemical Pharmacology

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“…No signal for α2 and β4 mRNA was detected. Le Novere et al, [65] obtained virtually identical results in a study that measured in situ hybridization of the α3, α4, α5, α6, β2, β3 and β4 mRNAs in catecholamine-rich rat brain regions. These findings suggest that more than one nAChR subtype is expressed in dopaminergic neurons, but this conclusion must be treated with caution because the in situ hybridization strategies that were used in the studies discussed above lack the anatomical resolution required to determine whether specific cell types express a given mRNA.…”

mentioning

confidence: 74%

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

Grady

Salminen

Laverty

et al. 2007

Biochemical Pharmacology

232

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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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“…Some subunits are widely expressed at medium or low levels, like ␣4 and ␤2 (for the rodent, see Wada et al, 1989) while others like ␣2, ␣3, ␣6, or ␤4, are expressed at high levels yet in a limited number of structures (for the rodent, see Wada et al, 1989;Dineley-Miller and Patrick, 1992;Le Novère et al, 1996). In addition, the study of developmental patterns revealed transient mRNAs subunit expressions (such as ␣3 mRNA in the cortex, Zoli et al, 1995).…”

Section: Promoters and Regulation Of Expressionmentioning

confidence: 99%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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Neuronal Nicotinic Receptor a6 Subunit mRNA is Selectively Concentrated in Catecholaminergic Nuclei of the Rat Brain

Cited by 352 publications

References 59 publications

Nicotinic receptors as CNS targets for Parkinson's disease

Nicotinic receptors as CNS targets for Parkinson's disease

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

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

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