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Molecular Underpinnings of Neuronal Nicotinic Acetylcholine Receptor Expression

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Nicotinic Receptors

Part of the book series: The Receptors ((REC,volume 26))

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are critical signaling molecules in a broad variety of fundamental biological processes. In order for cholinergic signaling to function normally, the receptors must be expressed in the appropriate cells at the appropriate times. Expression of the receptors is regulated at many levels from transcription of the receptor subunit genes to posttranslational modifications of individual subunits. Regulating nAChR expression is further complicated because of the large number of genes encoding nAChR subunits, most of which, but not all, are located on distinct chromosomes. Here, we describe molecular events that underlie expression of nAChR subunit genes. We begin with a survey of the transcriptional mechanisms involved in nAChR subunit gene expression including a review of CHRNA5/A3/B4 cluster expression. An update on two emerging fields of investigation, microRNA and epigenetic regulation of nAChR expression, is provided followed by an overview of mechanisms involved in the nicotine-mediated upregulation of nAChR expression. Regulation of nAChR subunit expression is of fundamental importance as it underlies subunit availability, which impacts individual receptor subtype composition and thus, the biophysical properties of the nAChRs.

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References

  1. Albuquerque EX, et al. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev. 2009;89(1):73–120.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Woolf NJ, Butcher LL. Cholinergic systems mediate action from movement to higher consciousness. Behav Brain Res. 2011;221(2):488–98.

    CAS  PubMed  Google Scholar 

  3. Simon-Keller K, et al. Targeting the fetal acetylcholine receptor in rhabdomyosarcoma. Expert Opin Ther Targets. 2013;17(2):127–38.

    CAS  PubMed  Google Scholar 

  4. de Almeida JP, Saldanha C. Nonneuronal cholinergic system in human erythrocytes: biological role and clinical relevance. J Membr Biol. 2010;234(3):227–34.

    CAS  PubMed  Google Scholar 

  5. Wallace TL, Bertrand D. Alpha7 neuronal nicotinic receptors as a drug target in schizophrenia. Expert Opin Ther Targets. 2013;17(2):139–55.

    CAS  PubMed  Google Scholar 

  6. Hurst R, Rollema H, Bertrand D. Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacol Ther. 2013;137(1):22–54.

    CAS  PubMed  Google Scholar 

  7. Buckingham SD, et al. Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol Rev. 2009;61(1):39–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Improgo MR, Tapper AR, Gardner PD. Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer. Biochem Pharmacol. 2011;82(8):1015–21.

    CAS  PubMed  Google Scholar 

  9. Steinlein OK. Animal models for autosomal dominant frontal lobe epilepsy: on the origin of seizures. Expert Rev Neurother. 2010;10(12):1859–67.

    CAS  PubMed  Google Scholar 

  10. Le Novere N, Corringer PJ, Changeux JP. The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J Neurobiol. 2002;53(4):447–56.

    PubMed  Google Scholar 

  11. Corringer PJ, Le Novere N, Changeux JP. Nicotinic receptors at the amino acid level. Annu Rev Pharmacol Toxicol. 2000;40:431–58.

    CAS  PubMed  Google Scholar 

  12. Eisele JL, et al. Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities. Nature. 1993;366(6454):479–83.

    CAS  PubMed  Google Scholar 

  13. McGehee DS, Role LW. Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu Rev Physiol. 1995;57:521–46.

    CAS  PubMed  Google Scholar 

  14. Wang JC, et al. Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol Psychiatry. 2009;14(5):501–10.

    CAS  PubMed  Google Scholar 

  15. Saccone NL, et al. Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(4):453–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Rozycka A, et al. A transcript coding for a partially duplicated form of alpha7 nicotinic acetylcholine receptor is absent from the CD4+ T-lymphocytes of patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Folia Neuropathol. 2013;51(1):65–75.

    CAS  PubMed  Google Scholar 

  17. Perl O, et al. The alpha7 nicotinic acetylcholine receptor in schizophrenia: decreased mRNA levels in peripheral blood lymphocytes. FASEB J. 2003;17(13):1948–50.

    CAS  PubMed  Google Scholar 

  18. Falvella FS, et al. Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk. Clin Cancer Res. 2009;15(5):1837–42.

    CAS  PubMed  Google Scholar 

  19. Gaimarri A, et al. Regulation of neuronal nicotinic receptor traffic and expression. Brain Res Rev. 2007;55(1):134–43.

    CAS  PubMed  Google Scholar 

  20. Son JH, Winzer-Serhan UH. Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs in rat hippocampal GABAergic interneurons. J Comp Neurol. 2008;511(2):286–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Son JH, Winzer-Serhan UH. Postnatal expression of alpha2 nicotinic acetylcholine receptor subunit mRNA in developing cortex and hippocampus. J Chem Neuroanat. 2006;32(2–4):179–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Ishii K, Wong JK, Sumikawa K. Comparison of alpha2 nicotinic acetylcholine receptor subunit mRNA expression in the central nervous system of rats and mice. J Comp Neurol. 2005;493(2):241–60.

    CAS  PubMed  Google Scholar 

  23. Azam L, et al. Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs within midbrain dopamine neurons. J Comp Neurol. 2002;444(3):260–74.

    CAS  PubMed  Google Scholar 

  24. Keiger CJ, Walker JC. Individual variation in the expression profiles of nicotinic receptors in the olfactory bulb and trigeminal ganglion and identification of alpha2, alpha6, alpha9, and beta3 transcripts. Biochem Pharmacol. 2000;59(3):233–40.

    CAS  PubMed  Google Scholar 

  25. Milton NG, et al. Differential regulation of neuronal nicotinic acetylcholine receptor subunit gene promoters by Brn-3 POU family transcription factors. Biochem J. 1996;317(Pt 2):419–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Greenbaum L, Lerer B. Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions. Mol Psychiatry. 2009;14:912–45.

    CAS  PubMed  Google Scholar 

  27. Gotti C, Clementi F. Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol. 2004;74(6):363–96.

    CAS  PubMed  Google Scholar 

  28. Rust G, et al. Expression of neuronal nicotinic acetylcholine receptor subunit genes in the rat autonomic nervous system. Eur J Neurosci. 1994;6(3):478–85.

    CAS  PubMed  Google Scholar 

  29. Zoli M, et al. Developmental regulation of nicotinic ACh receptor subunit mRNAs in the rat central and peripheral nervous systems. J Neurosci. 1995;15(3 Pt 1):1912–39.

    CAS  PubMed  Google Scholar 

  30. Wada E, et al. Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J Comp Neurol. 1989;284(2):314–35.

    CAS  PubMed  Google Scholar 

  31. Flores CM, et al. Neuronal nicotinic rceptor expression in sensory neurons of the rat trigeminal ganglion: demonstration of α3/β4, a novel subtype in the mammalian nervous system. J Neurosci. 1996;16:7892–901.

    CAS  PubMed  Google Scholar 

  32. Liu L, et al. Neuronal nicotinic acetylcholine receptors in rat trigeminal ganglia. Brain Res. 1998;809(2):238–45.

    CAS  PubMed  Google Scholar 

  33. Keiger CJ, et al. Developmental expression of nicotinic receptors in the chick and human spinal cord. J Comp Neurol. 2003;455(1):86–99.

    CAS  PubMed  Google Scholar 

  34. Hellstrom-Lindahl E, et al. Regional distribution of nicotinic receptors during prenatal development of human brain and spinal cord. Brain Res Dev Brain Res. 1998;108(1–2):147–60.

    CAS  PubMed  Google Scholar 

  35. Gahring LC, et al. Mouse strain-specific nicotinic acetylcholine receptor expression by inhibitory interneurons and astrocytes in the dorsal hippocampus. J Comp Neurol. 2004;468(3):334–46.

    CAS  PubMed  Google Scholar 

  36. Winzer-Serhan UH, Leslie FM. Codistribution of nicotinic acetylcholine receptor subunit alpha3 and beta4 mRNAs during rat brain development. J Comp Neurol. 1997;386(4):540–54.

    CAS  PubMed  Google Scholar 

  37. Rogers SW, et al. Neuronal nicotinic acetylcholine receptor expression by O2A/oligodendrocyte progenitor cells. Glia. 2001;33(4):306–13.

    CAS  PubMed  Google Scholar 

  38. Benhammou K, et al. [(3)H]Nicotine binding in peripheral blood cells of smokers is correlated with the number of cigarettes smoked per day. Neuropharmacology. 2000;39(13):2818–29.

    CAS  PubMed  Google Scholar 

  39. Flora A, et al. Neuronal and extraneuronal expression and regulation of the human alpha5 nicotinic receptor subunit gene. J Neurochem. 2000;75(1):18–27.

    CAS  PubMed  Google Scholar 

  40. Glushakov AV, et al. Distribution of neuronal nicotinic acetylcholine receptors containing different alpha-subunits in the submucosal plexus of the guinea-pig. Auton Neurosci. 2004;110(1):19–26.

    CAS  PubMed  Google Scholar 

  41. Macklin KD, et al. Human vascular endothelial cells express functional nicotinic acetylcholine receptors. J Pharmacol Exp Ther. 1998;287(1):435–9.

    CAS  PubMed  Google Scholar 

  42. Wang Y, et al. Human bronchial epithelial and endothelial cells express alpha7 nicotinic acetylcholine receptors. Mol Pharmacol. 2001;60(6):1201–9.

    CAS  PubMed  Google Scholar 

  43. Maus AD, et al. Human and rodent bronchial epithelial cells express functional nicotinic acetylcholine receptors. Mol Pharmacol. 1998;54(5):779–88.

    CAS  PubMed  Google Scholar 

  44. Improgo MR, et al. From smoking to lung cancer: the CHRNA5/A3/B4 connection. Oncogene. 2010;29(35):4874–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Benfante R, et al. Transcription factor PHOX2A regulates the human α3 nicotinic receptor subunit gene promoter. J Biol Chem. 2007;282(18):13290–302.

    CAS  PubMed  Google Scholar 

  46. Shimakura J, et al. The transcription factor Cdx2 regulates the intestine-specific expression of human peptide transporter 1 through functional interaction with Sp1. Biochem Pharmacol. 2006;71(11):1581–8.

    CAS  PubMed  Google Scholar 

  47. Yang X, et al. Characterization of an acetylcholine receptor alpha 3 gene promoter and its activation by the POU domain factor SCIP/Tst-1. J Biol Chem. 1994;269(14):10252–64.

    CAS  PubMed  Google Scholar 

  48. Fyodorov D, Deneris E. The POU domain of SCIP/Tst-1/Oct-6 is sufficient for activation of an acetylcholine receptor promoter. Mol Cell Biol. 1996;16(9):5004–14.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. McDonough J, Deneris E. Beta43′: an enhancer displaying neural-restricted activity is located in the 3′-untranslated exon of the rat nicotinic acetylcholine receptor beta4 gene. J Neurosci. 1997;17(7):2273–83.

    CAS  PubMed  Google Scholar 

  50. McDonough J, et al. Regulation of transcription in the neuronal nicotinic receptor subunit gene cluster by a neuron-selective enhancer and ETS domain factors. J Biol Chem. 2000;275(37):28962–70.

    CAS  PubMed  Google Scholar 

  51. Fyodorov D, Nelson T, Deneris E. Pet-1, a novel ETS domain factor that can activate neuronal nAchR gene transcription. J Neurobiol. 1998;34(2):151–63.

    CAS  PubMed  Google Scholar 

  52. Yang X, et al. Elements between the protein-coding regions of the adjacent beta 4 and alpha 3 acetylcholine receptor genes direct neuron-specific expression in the central nervous system. J Neurobiol. 1997;32(3):311–24.

    CAS  PubMed  Google Scholar 

  53. Fuentes Medel YF, Gardner PD. Transcriptional repression by a conserved intronic sequence in the nicotinic receptor alpha3 subunit gene. J Biol Chem. 2007;282(26):19062–70.

    Google Scholar 

  54. Improgo MR, et al. ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. Mol Cancer Res. 2010;8(2):194–203.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Changeux J, Edelstein SJ. Allosteric mechanisms in normal and pathological nicotinic acetylcholine receptors. Curr Opin Neurobiol. 2001;11(3):369–77.

    CAS  PubMed  Google Scholar 

  56. Watanabe H, Zoli M, Changeux JP. Promoter analysis of the neuronal nicotinic acetylcholine receptor alpha4 gene: methylation and expression of the transgene. Eur J Neurosci. 1998;10(7):2244–53.

    CAS  PubMed  Google Scholar 

  57. Eggert M, et al. Nicotinic acetylcholine receptor subunits alpha4 and alpha5 associated with smoking behaviour and lung cancer are regulated by upstream open reading frames. PLoS One. 2013;8(7):e66157.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Wada E, et al. The distribution of mRNA encoded by a new member of the neuronal nicotinic acetylcholine receptor gene family (alpha 5) in the rat central nervous system. Brain Res. 1990;526(1):45–53.

    CAS  PubMed  Google Scholar 

  59. Boulter J, et al. Alpha 3, alpha 5, and beta 4: three members of the rat neuronal nicotinic acetylcholine receptor-related gene family form a gene cluster. J Biol Chem. 1990;265(8):4472–82.

    CAS  PubMed  Google Scholar 

  60. Conroy WG, Vernallis AB, Berg DK. The alpha 5 gene product assembles with multiple acetylcholine receptor subunits to form distinctive receptor subtypes in brain. Neuron. 1992;9(4):679–91.

    CAS  PubMed  Google Scholar 

  61. Improgo MR, et al. The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: Dual role in nicotine addiction and lung cancer. Prog Neurobiol. 2010;92:212–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Bailey CD, et al. The nicotinic acetylcholine receptor alpha5 subunit plays a key role in attention circuitry and accuracy. J Neurosci. 2010;30(27):9241–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Fowler CD, et al. Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011;471(7340):597–601.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Frahm S, et al. Aversion to nicotine is regulated by the balanced activity of β4 and α5 nicotinic receptor subunits in the medial habenula. Neuron. 2011;70(3):522–35.

    CAS  PubMed  Google Scholar 

  65. Exley R, et al. Striatal α5 nicotinic receptor subunit regulates dopamine transmission in dorsal striatum. J Neurosci. 2012;32(7):2352–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Moretti M, et al. Nicotinic acetylcholine receptor subtypes expression during rat retina development and their regulation by visual experience. Mol Pharmacol. 2004;66(1):85–96.

    CAS  PubMed  Google Scholar 

  67. Campos-Caro A, et al. Multiple functional Sp1 domains in the minimal promoter region of the neuronal nicotinic receptor alpha5 subunit gene. J Biol Chem. 1999;274(8):4693–701.

    CAS  PubMed  Google Scholar 

  68. Flora A, et al. Transcriptional regulation of the human alpha5 nicotinic receptor subunit gene in neuronal and non-neuronal tissues. Eur J Pharmacol. 2000;393(1–3):85–95.

    CAS  PubMed  Google Scholar 

  69. Gotti C, et al. Brain neuronal nicotinic receptors as new targets for drug discovery. Curr Pharm Des. 2006;12(4):407–28.

    CAS  PubMed  Google Scholar 

  70. Champtiaux N, et al. Distribution and pharmacology of alpha 6-containing nicotinic acetylcholine receptors analyzed with mutant mice. J Neurosci. 2002;22(4):1208–17.

    CAS  PubMed  Google Scholar 

  71. Salminen O, et al. Pharmacology of alpha-conotoxin MII-sensitive subtypes of nicotinic acetylcholine receptors isolated by breeding of null mutant mice. Mol Pharmacol. 2007;71(6):1563–71.

    CAS  PubMed  Google Scholar 

  72. Ebihara M, et al. Genomic organization and promoter analysis of the human nicotinic acetylcholine receptor alpha6 subunit (CHNRA6) gene: Alu and other elements direct transcriptional repression. Gene. 2002;298(1):101–8.

    CAS  PubMed  Google Scholar 

  73. Munguba GC, et al. Effects of glaucoma on Chrna6 expression in the retina. Curr Eye Res. 2013;38(1):150–7.

    CAS  PubMed  Google Scholar 

  74. Nagavarapu U, Danthi S, Boyd RT. Characterization of a rat neuronal nicotinic acetylcholine receptor alpha7 promoter. J Biol Chem. 2001;276(20):16749–57.

    CAS  PubMed  Google Scholar 

  75. Carrasco-Serrano C, et al. GC- and E-box motifs as regulatory elements in the proximal promoter region of the neuronal nicotinic receptor alpha7 subunit gene. J Biol Chem. 1998;273(32):20021–8.

    CAS  PubMed  Google Scholar 

  76. Matter JM, et al. On the transcriptional regulation of neuronal nAChR genes. J Physiol Paris. 1998;92(3–4):245–8.

    CAS  PubMed  Google Scholar 

  77. Gault J, et al. Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics. 1998;52(2):173–85.

    CAS  PubMed  Google Scholar 

  78. Criado M, et al. Differential expression of alpha-bungarotoxin-sensitive neuronal nicotinic receptors in adrenergic chromaffin cells: a role for transcription factor Egr-1. J Neurosci. 1997;17(17):6554–64.

    CAS  PubMed  Google Scholar 

  79. Reynolds PR, Hoidal JR. Temporal-spatial expression and transcriptional regulation of alpha7 nicotinic acetylcholine receptor by thyroid transcription factor-1 and early growth response factor-1 during murine lung development. J Biol Chem. 2005;280(37):32548–54.

    CAS  PubMed  Google Scholar 

  80. De Koninck P, Cooper E. Differential regulation of neuronal nicotinic ACh receptor subunit genes in cultured neonatal rat sympathetic neurons: specific induction of alpha 7 by membrane depolarization through a Ca2+/calmodulin-dependent kinase pathway. J Neurosci. 1995;15(12):7966–78.

    PubMed  Google Scholar 

  81. Zhou X, et al. Brain-derived neurotrophic factor and trkB signaling in parasympathetic neurons: relevance to regulating alpha7-containing nicotinic receptors and synaptic function. J Neurosci. 2004;24(18):4340–50.

    CAS  PubMed  Google Scholar 

  82. Yang X, et al. A cysteine-rich isoform of neuregulin controls the level of expression of neuronal nicotinic receptor channels during synaptogenesis. Neuron. 1998;20(2):255–70.

    CAS  PubMed  Google Scholar 

  83. Aztiria E, Gotti C, Domenici L. Alpha7 but not alpha4 AChR subunit expression is regulated by light in developing primary visual cortex. J Comp Neurol. 2004;480(4):378–91.

    CAS  PubMed  Google Scholar 

  84. Mexal S, et al. Differential regulation of alpha7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers. J Mol Neurosci. 2010;40(1–2):185–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Schoepfer R, et al. Brain alpha-bungarotoxin binding protein cDNAs and MAbs reveal subtypes of this branch of the ligand-gated ion channel gene superfamily. Neuron. 1990;5(1):35–48.

    CAS  PubMed  Google Scholar 

  86. Simmons DD, Morley BJ. Spatial and temporal expression patterns of nicotinic acetylcholine α9 and α10 subunits in the embryonic and early postnatal inner ear. Neuroscience. 2011;194:326–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Lustig LR. Nicotinic acetylcholine receptor structure and function in the efferent auditory system. Anat Rec A Discov Mol Cell Evol Biol. 2006;288(4):424–34.

    PubMed  Google Scholar 

  88. Vetter DE, et al. The alpha10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system. Proc Natl Acad Sci U S A. 2007;104(51):20594–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Plazas PV, et al. Stoichiometry of the alpha9alpha10 nicotinic cholinergic receptor. J Neurosci. 2005;25(47):10905–12.

    CAS  PubMed  Google Scholar 

  90. Lips KS, Pfeil U, Kummer W. Coexpression of alpha 9 and alpha 10 nicotinic acetylcholine receptors in rat dorsal root ganglion neurons. Neuroscience. 2002;115(1):1–5.

    CAS  PubMed  Google Scholar 

  91. Lustig LR, et al. Molecular cloning and mapping of the human nicotinic acetylcholine receptor alpha10 (CHRNA10). Genomics. 2001;73(3):272–83.

    CAS  PubMed  Google Scholar 

  92. Valor LM, et al. Transcriptional regulation by activation and repression elements located at the 5'-noncoding region of the human alpha9 nicotinic receptor subunit gene. J Biol Chem. 2003;278(39):37249–55.

    CAS  PubMed  Google Scholar 

  93. Picciotto MR, et al. Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature. 1998;391(6663):173–7.

    CAS  PubMed  Google Scholar 

  94. Dawson A, Miles MF, Damaj MI. The β2 nicotinic acetylcholine receptor subunit differentially influences ethanol behavioral effects in the mouse. Alcohol. 2013;47(2):85–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. De Fusco M, et al. The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet. 2000;26(3):275–6.

    PubMed  Google Scholar 

  96. Bessis A, et al. Promoter elements conferring neuron-specific expression of the β2-subunit of the neuronal nicotinic acetylcholine receptor studied in vitro and in transgenic mice. Neuroscience. 1995;69(3):807–19.

    CAS  PubMed  Google Scholar 

  97. Lueders KK, et al. Genomic organization and mapping of the human and mouse neuronal beta2-nicotinic acetylcholine receptor genes. Mamm Genome. 1999;10(9):900–5.

    CAS  PubMed  Google Scholar 

  98. Bessis A, et al. The neuron-restrictive silencer element: a dual enhancer/silencer crucial for patterned expression of a nicotinic receptor gene in the brain. Proc Natl Acad Sci U S A. 1997;94:5906–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Hoft NR, et al. CHRNB2 promoter region: association with subjective effects to nicotine and gene expression differences. Genes Brain Behav. 2011;10(2):176–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Oh SH, Kim CS, Song JJ. Gene expression and plasticity in the rat auditory cortex after bilateral cochlear ablation. Acta Otolaryngol. 2007;127(4):341–50.

    CAS  PubMed  Google Scholar 

  101. Hoft NR, et al. Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample. Neuropsychopharmacology. 2009;34(3):698–706.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Mandelzys A, et al. The developmental increase in ACh current densities on rat sympathetic neurons correlates with changes in nicotinic ACh receptor alpha-subunit gene expression and occurs independent of innervation. J Neurosci. 1994;14(4):2357–64.

    CAS  PubMed  Google Scholar 

  103. Dineley-Miller K, Patrick J. Gene transcripts for the nicotinic acetylcholine receptor subunit, beta4, are distributed in multiple areas of the rat central nervous system. Brain Res Mol Brain Res. 1992;16(3–4):339–44.

    CAS  PubMed  Google Scholar 

  104. Di Angelantonio S, et al. Molecular biology and electrophysiology of neuronal nicotinic receptors of rat chromaffin cells. Eur J Neurosci. 2003;17(11):2313–22.

    PubMed  Google Scholar 

  105. Melnikova IN, Gardner PD. The signal transduction pathway underlying ion channel gene regulation by SP1-C-Jun interactions. J Biol Chem. 2001;276(22):19040–5.

    CAS  PubMed  Google Scholar 

  106. Melnikova IN, et al. Synergistic transcriptional activation by Sox10 and Sp1 family members. Neuropharmacology. 2000;39(13):2615–23.

    CAS  PubMed  Google Scholar 

  107. Melnikova IN, Yang Y, Gardner PD. Interactions between regulatory proteins that bind to the nicotinic receptor beta4 subunit gene promoter. Eur J Pharmacol. 2000;393(1–3):75–83.

    CAS  PubMed  Google Scholar 

  108. Scofield MD, et al. Transcription factor assembly on the nicotinic receptor beta4 subunit gene promoter. Neuroreport. 2008;19(6):687–90.

    CAS  PubMed  Google Scholar 

  109. Du Q, Tomkinson AE, Gardner PD. Transcriptional regulation of neuronal nicotinic acetylcholine receptor genes. A possible role for the DNA-binding protein Puralpha. J Biol Chem. 1997;272(23):14990–5.

    CAS  PubMed  Google Scholar 

  110. Du Q, Melnikova IN, Gardner PD. Differential effects of heterogeneous nuclear ribonucleoprotein K on Sp1- and Sp3-mediated transcriptional activation of a neuronal nicotinic acetylcholine receptor promoter. J Biol Chem. 1998;273(31):19877–83.

    CAS  PubMed  Google Scholar 

  111. Krecic AM, Swanson MS. hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol. 1999;11:363–71.

    CAS  PubMed  Google Scholar 

  112. Da Silva N, Bharti A, Shelley CS. hnRNP-K and Purα act together to repress the transcriptional activity of the CD43 gene promoter. Blood. 2002;100(10):3536–44.

    PubMed  Google Scholar 

  113. Bruschweiler-Li L, et al. Temporally- and spatially-regulated transcriptional activity of the nicotinic acetylcholine receptor beta4 subunit gene promoter. Neuroscience. 2010;166(3):864–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Scofield MD, Tapper AR, Gardner PD. A transcriptional regulatory element critical for CHRNB4 promoter activity in vivo. Neuroscience. 2010;170(4):1056–64.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Fornasari D, et al. Transcriptional regulation of neuronal nicotinic receptor subunit genes. In: Arneric SP, Brioni JD, editors. Neuronal nicotinic receptors: pharmacology and therapeutic opportunities. Wilmington, DE: Wiley-Liss Inc.; 1998.

    Google Scholar 

  116. Fornasari D, et al. Structural and functional characterization of the human alpha3 nicotinic subunit gene promoter. Mol Pharmacol. 1997;51(2):250–61.

    CAS  PubMed  Google Scholar 

  117. Pugh BF, Tjian R. Transcription from a TATA-less promoter requires a multisubunit TFIID complex. Genes Dev. 1991;5:1935–9145.

    CAS  PubMed  Google Scholar 

  118. Liu Q, et al. Cell type-specific activation of neuronal nicotinic acetylcholine receptor subunit genes by Sox10. J Neurosci. 1999;19(22):9747–55.

    CAS  PubMed  Google Scholar 

  119. Corriveau RA, Berg DK. Coexpression of multiple acetylcholine receptor genes in neurons: quantitation of transcripts during development. J Neurosci. 1993;13:2662–71.

    CAS  PubMed  Google Scholar 

  120. Zhou Y, Deneris E, Zigmond RE. Differential regulation of levels of nicotinic receptor subunit transcripts in adult sympathetic neurons after axotomy. J Neurobiol. 1998;34(2):164–78.

    CAS  PubMed  Google Scholar 

  121. Xu X, Scott MM, Deneris ES. Shared long-range regulatory elements coordinate expression of a gene cluster encoding nicotinic receptor heteromeric subtypes. Mol Cell Biol. 2006;26(15):5636–49.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Friedman RC, et al. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92–105.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Cao X, et al. Noncoding RNAs in the mammalian central nervous system. Annu Rev Neurosci. 2006;29:77–103.

    CAS  PubMed  Google Scholar 

  124. Bicker S, Schratt G. microRNAs: tiny regulators of synapse function in development and disease. J Cell Mol Med. 2008;12(5A):1466–76.

    CAS  PubMed  Google Scholar 

  125. Fiore R, Siegel G, Schratt G. MicroRNA function in neuronal development, plasticity and disease. Biochim Biophys Acta. 2008;1779(8):471–8.

    CAS  PubMed  Google Scholar 

  126. Ameres SL, Zamore PD. Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol. 2013;14(8):475–88.

    CAS  PubMed  Google Scholar 

  127. Balaraman S, Winzer-Serhan UH, Miranda RC. Opposing actions of ethanol and nicotine on microRNAs are mediated by nicotinic acetylcholine receptors in fetal cerebral cortical-derived neural progenitor cells. Alcohol Clin Exp Res. 2012;36(10):1669–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Schembri F, et al. MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc Natl Acad Sci U S A. 2009;107(7):2319–24.

    Google Scholar 

  129. Izzotti A, et al. Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke. FASEB J. 2009;23(3):806–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Shan H, et al. Downregulation of miR-133 and miR-590 contributes to nicotine-induced atrial remodelling in canines. Cardiovasc Res. 2009;83(3):465–72.

    CAS  PubMed  Google Scholar 

  131. Huang W, Li MD. Nicotine modulates expression of miR-140*, which targets the 3′-untranslated region of dynamin 1 gene (Dnm1). Int J Neuropsychopharmacol. 2009;12(4):537–46.

    CAS  PubMed  Google Scholar 

  132. Lippi G, et al. Targeting of the Arpc3 actin nucleation factor by miR-29a/b regulates dendritic spine morphology. J Cell Biol. 2011;194(6):889–904.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Simon D, et al. The microRNA miR-1 regulates a MEF-2-dependent retrograde signal at neuromuscular junctions. Cell. 2008;2133(5):903–15.

    Google Scholar 

  134. Jablonka E. Epigenetic variations in heredity and evolution. Clin Pharmacol Ther. 2012;92(6):683–8.

    CAS  PubMed  Google Scholar 

  135. Rando OJ, Verstrepen KJ. Timescales of genetic and epigenetic inheritance. Cell. 2007;128(4):655–68.

    CAS  PubMed  Google Scholar 

  136. Van Speybroeck L. From epigenesis to epigenetics: the case of C. H. Waddington. Ann N Y Acad Sci. 2002;981:61–81.

    PubMed  Google Scholar 

  137. Brower V. Epigenetics: unravelling the cancer code. Nature. 2011;471(7339):S12–3.

    CAS  PubMed  Google Scholar 

  138. Stower H. Epigenetics: dynamic DNA methylation. Nat Rev Genet. 2012;13(2):75.

    CAS  PubMed  Google Scholar 

  139. Canastar A, et al. Promoter methylation and tissue-specific transcription of the alpha7 nicotinic receptor gene, CHRNA7. J Mol Neurosci. 2012;47(2):389–400.

    CAS  PubMed  Google Scholar 

  140. Maloku E, et al. Selective α4β2 nicotinic acetylcholine receptor agonists target epigenetic mechanisms in cortical GABAergic neurons. Neuropsychopharmacology. 2011;36(7):1366–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Paliwal A, et al. Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer. Cancer Res. 2010;70(7):2779–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Scherf DB, et al. Epigenetic screen identifies genotype-specific promoter DNA methylation and oncogenic potential of CHRNB4. Oncogene. 2012;32:3329–38.

    PubMed Central  PubMed  Google Scholar 

  143. Caporaso N, et al. Genome-wide and candidate gene association study of cigarette smoking behaviors. PLoS One. 2009;4(2):e4653.

    PubMed Central  PubMed  Google Scholar 

  144. Yasui DH, et al. 15q11.2-13.3 chromatin analysis reveals epigenetic regulation of CHRNA7 with deficiencies in Rett and autism brain. Hum Mol Genet. 2011;20(22):4311–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Chahrour M, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320(5880):1224–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Bencherif M, et al. Mechanisms of up-regulation of neuronal nicotinic acetylcholine receptors in clonal cell lines and primary cultures of fetal rat brain. J Pharmacol Exp Ther. 1995;275(2):987–94.

    CAS  PubMed  Google Scholar 

  147. Govind AP, Vezina P, Green WN. Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol. 2009;78(7):756–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Fenster CP, et al. Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine. J Neurosci. 1999;19(12):4804–14.

    CAS  PubMed  Google Scholar 

  149. Buisson B, Bertrand D. Chronic exposure to nicotine upregulates the human (alpha)4((beta)2 nicotinic acetylcholine receptor function. J Neurosci. 2001;21(6):1819–29.

    CAS  PubMed  Google Scholar 

  150. Marks MJ, et al. Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci. 1992;12(7):2765–84.

    CAS  PubMed  Google Scholar 

  151. Huang LZ, Winzer-Serhan UH. Chronic neonatal nicotine upregulates heteromeric nicotinic acetylcholine receptor binding without change in subunit mRNA expression. Brain Res. 2006;1113(1):94–109.

    CAS  PubMed  Google Scholar 

  152. Srinivasan R, et al. Nicotine up-regulates alpha4beta2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning. J Gen Physiol. 2010;137(1):59–79.

    Google Scholar 

  153. Peng X, et al. Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol Pharmacol. 1994;46:523–30.

    CAS  PubMed  Google Scholar 

  154. Darsow T, et al. Exocytic trafficking is required for nicotine-induced up-regulation of alpha 4 beta 2 nicotinic acetylcholine receptors. J Biol Chem. 2005;280(18):18311–20.

    CAS  PubMed  Google Scholar 

  155. Nashmi R, et al. Assembly of α4β2 nicotinic acetylcholine receptors assessed with functional fluorescently labeled subunits: effects of localization, trafficking, and nicotine-induced upregulation in clonal mammalian cells and in cultured midbrain neurons. J Neurosci. 2003;23:11554–67.

    CAS  PubMed  Google Scholar 

  156. Sallette J, et al. Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron. 2005;46(4):595–607.

    CAS  PubMed  Google Scholar 

  157. Ficklin MB, Zhao S, Feng G. Ubiquilin-1 regulates nicotine-induced up-regulation of neuronal nicotinic acetylcholine receptors. J Biol Chem. 2005;280:34088–95.

    CAS  PubMed  Google Scholar 

  158. Rezvani K, et al. Nicotine regulates multiple synaptic proteins by inhibiting proteosomal activity. J Neurosci. 2007;27:10508–19.

    CAS  PubMed  Google Scholar 

  159. Nelson ME, Kuryatov A, Choi CH, Zhou Y, Lindstrom J. Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors. J Mol Pharmacol. 2003;63(2):332–41.

    CAS  Google Scholar 

  160. Moroni M, et al. alpha4beta2 nicotinc receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine. Mol Pharmacol. 2006;70:755–68.

    CAS  PubMed  Google Scholar 

  161. Vallejo Y, et al. Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J Neurosci. 2005;25(23):5563–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Walsh H, et al. Up-regulation of nicotinic receptors by nicotine varies with receptor subtype. J Biol Chem. 2008;283(10):6022–32.

    CAS  PubMed  Google Scholar 

  163. Columbo SF, et al. Biogenesis, trafficking and up-regulation of nicotinic ACh recpetors. Biochem Pharmacol. 2013;86:1063–73.

    Google Scholar 

  164. Kuryatov A, et al. Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Mol Pharmacol. 2005;68(6):1839–51.

    CAS  PubMed  Google Scholar 

  165. Govind AP, Walsh H, Green WN. Nicotine-induced upregulation of native neuronal nicotinic receptors is caused by multiple mechanisms. J Neurosci. 2012;32(6):2227–38.

    CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA

    Michael D. Scofield Ph.D.

  2. Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA, 01604, USA

    Paul D. Gardner Ph.D.

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  1. Michael D. Scofield Ph.D.
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  2. Paul D. Gardner Ph.D.
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Correspondence to Paul D. Gardner Ph.D. .

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  1. Department of Neurobiology SHEL 1006, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Robin A.J. Lester

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Scofield, M.D., Gardner, P.D. (2014). Molecular Underpinnings of Neuronal Nicotinic Acetylcholine Receptor Expression. In: Lester, R. (eds) Nicotinic Receptors. The Receptors, vol 26. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1167-7_3

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