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. 2006 Jan 13;7(4):E885–E894. doi: 10.1208/aapsj070486

Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells

Lorise C Gahring 1,3,, Scott W Rogers 1,2
PMCID: PMC2750958  PMID: 16594641

Abstract

Of the thousands of proven carcinogens and toxic agents contained within a cigarette, nicotine, while being the addictive agent, is often viewed as the least harmful of these compounds. Nicotine is a lipophilic molecule whose effects on neuronal nicotinic acetylcholine receptors (nAChR) have been primarily focused on its physiologic impact within the confines of the brain and peripheral nervous system. However, recently, many studies have found neuronal nAChRs to be expressed on many different nonneuronal cell types throughout the body, where increasing evidence suggests they have important roles in determining the consequences of nicotine use on multiple organs systems and diseases as diverse as ulcerative colitis, chronic pulmonary obstructive disease, and diabetes, as well as the neurologic disorders of Parkinson’s and Alzheimer’s disease. This review highlights current evidence for the expression of peripheral nAChRs in cells other than neurons and how they participate in fundamental processes, such as inflammation. Understanding these processes may offer novel therapeutic strategies to approach inflammatory diseases, as well as precautions in the design of interventional drugs.

Keywords: nicotine, inflammation, nicotinic receptors, nonneuronal

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References

  • 1.Kellar KJ, Whitehouse PJ, Martino-Barrows AM, Marcus K, Price DL. Muscarinic and nicotinic cholinergic binding sites in Alzheimer’s disease cerebral cortex. Brain Res. 1987;436:62–68. doi: 10.1016/0006-8993(87)91556-3. [DOI] [PubMed] [Google Scholar]
  • 2.Rezvani AH, Levin ED. Cognitive effects of nicotine. Biol Psychiatry. 2001;49:258–267. doi: 10.1016/S0006-3223(00)01094-5. [DOI] [PubMed] [Google Scholar]
  • 3.Sabbagh MN, Lukas RJ, Sparks DL, Reid RT. The nicotinic acetylcholine receptor, smoking, and Alzheimer’s disease. J Alzheimers Dis. 2002;4:317–325. doi: 10.3233/jad-2002-4407. [DOI] [PubMed] [Google Scholar]
  • 4.O’Neill MJ, Murray TK, Lakics V, Visanji NP, Duty S. The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration. Curr Drug Targets CNS Neurol Disord. 2002;1:399–411. doi: 10.2174/1568007023339166. [DOI] [PubMed] [Google Scholar]
  • 5.Quik M. Smoking, nicotine and Parkinson’s disease. Trends Neurosci. 2004;27:561–568. doi: 10.1016/j.tins.2004.06.008. [DOI] [PubMed] [Google Scholar]
  • 6.Shimohama S, Akaike A, Kimura J. Nicotine-induced protection against glutamate cytotoxicity. Nicotinic cholinergic receptor-mediated inhibition of nitric oxide formation. Ann N Y Acad Sci. 1996;777:356–361. doi: 10.1111/j.1749-6632.1996.tb34445.x. [DOI] [PubMed] [Google Scholar]
  • 7.Carlson NG, Bacchi A, Rogers SW, Gahring LC. Nicotine blocks TNF-alpha-mediated neuroprotection to NMDA by an alpha-bungarotoxin-sensitive pathway. J Neurobiol. 1998;35:29–36. doi: 10.1002/(SICI)1097-4695(199804)35:1<29::AID-NEU3>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  • 8.Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC. Inflammatory cytokines IL-1alpha, IL-1beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol. 1999;163:3963–3968. [PubMed] [Google Scholar]
  • 9.Dajas-Bailador FA, Lima PA, Wonnacott S. The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism. Neuropharmacology. 2000;39:2799–2807. doi: 10.1016/S0028-3908(00)00127-1. [DOI] [PubMed] [Google Scholar]
  • 10.Gahring LC, Meyer EL, Rogers SW. Nicotine-induced neuroprotection against N-methyl-D-aspartic acid or beta-amyloid peptide occur through independent mechanisms distinguished by pro-inflammatory cytokines. J Neurochem. 2003;87:1125–1136. doi: 10.1046/j.1471-4159.2003.02074.x. [DOI] [PubMed] [Google Scholar]
  • 11.Kihara T, Shimohama S, Urushitani M, et al. Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Res. 1998;792:331–334. doi: 10.1016/S0006-8993(98)00138-3. [DOI] [PubMed] [Google Scholar]
  • 12.Kihara T, Shimohama S, Sawada H, et al. Alpha7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to blockA beta-amyloid-induced neurotoxicity. J Biol Chem. 2001;276:13541–13546. doi: 10.1074/jbc.M008035200. [DOI] [PubMed] [Google Scholar]
  • 13.Pauly JR, Charriez CM, Guseva MV, Scheff SW. Nicotinic receptor modulation for neuroprotection and enhancement of functional recovery following brain injury or disease. Ann N Y Acad Sci. 2004;1035:316–334. doi: 10.1196/annals.1332.019. [DOI] [PubMed] [Google Scholar]
  • 14.Boulter J, O’Shea-Greenfield A, Duvoisin RM, et al. Alpha3, alpha5, and beta4: 3 members of the rat neuronal nicotinic acetylcholine receptor-related gene family form a gene cluster. J Biol Chem. 1990;265:4472–4482. [PubMed] [Google Scholar]
  • 15.Conti-Fine BM, Navaneetham D, Lei S, Maus AD. Neuronal nicotinic receptors in non-neuronal cells: new mediators of tobacco toxicity? Eur J Pharmacol. 2000;393:279–294. doi: 10.1016/S0014-2999(00)00036-4. [DOI] [PubMed] [Google Scholar]
  • 16.Sharma G, Vijayaraghavan S. Nicotinic receptor signaling in nonexcitable cells. J Neurobiol. 2002;53:524–534. doi: 10.1002/neu.10114. [DOI] [PubMed] [Google Scholar]
  • 17.Birtwistle J, Hall K. Does nicotine have beneficial effects in the treatment of certain diseases? Br J Nurs. 1996;5:1195–1202. doi: 10.12968/bjon.1996.5.19.1195. [DOI] [PubMed] [Google Scholar]
  • 18.Rubin DT, Hanauer SB. Smoking and inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2000;12:855–862. doi: 10.1097/00042737-200012080-00004. [DOI] [PubMed] [Google Scholar]
  • 19.Hilsden RJ, Hodgins DC, Timmer A, Sutherland LR. Helping patients with Crohn’s disease quit smoking. Am J Gastroenterol. 2000;95:352–358. doi: 10.1111/j.1572-0241.2000.t01-1-01789.x. [DOI] [PubMed] [Google Scholar]
  • 20.Wolf JM, Lashner BA. Inflammatory bowel disease: sorting out the treatment options. Cleve Clin J Med. 2002;69:621–626. doi: 10.3949/ccjm.69.8.621. [DOI] [PubMed] [Google Scholar]
  • 21.Lindstrom J. Neuronal nicotinic acetylcholine receptors. Ion Channels. 1996;4:377–450. doi: 10.1007/978-1-4899-1775-1_10. [DOI] [PubMed] [Google Scholar]
  • 22.Hogg RC, Raggenbass M, Bertrand D. Nicotinic acetylcholine receptors: from structure to brain function. Rev Physiol Biochem Pharmacol. 2003;147:1–46. doi: 10.1007/s10254-003-0005-1. [DOI] [PubMed] [Google Scholar]
  • 23.Woolf A, Burkhart K, Caraccio T, Litovitz T. Self-poisoning among adults using multiple transdermal nicotine patches. J Toxicol Clin Toxicol. 1996;34:691–698. doi: 10.3109/15563659609013830. [DOI] [PubMed] [Google Scholar]
  • 24.Alkondon M, Albuquerque EX. The nicotinic acetylcholine receptor subtypes and their function in the hippocampus and cerebral cortex. Prog Brain Res. 2004;145:109–120. doi: 10.1016/S0079-6123(03)45007-3. [DOI] [PubMed] [Google Scholar]
  • 25.Alkondon M, Albuquerque EX. Nicotinic acetylcholine receptor alpha7 and alpha4 beta2 subtypes differentially control GABAergic input to CA1 neurons in rat hippocampus. J Neurophysiol. 2001;86:3043–3055. doi: 10.1152/jn.2001.86.6.3043. [DOI] [PubMed] [Google Scholar]
  • 26.Alkondon M, Pereira EF, Albuquerque EX. Mapping the location of functional nicotinic and gamma-aminobutyric acidA receptors on hippocampal neurons. J Pharmacol Exp Ther. 1996;279:1491–1506. [PubMed] [Google Scholar]
  • 27.Hasselmo ME, Hay J, Ilyn M, Gorchetchnikov A. Neuromodulation, thetarhythm and rat spatial navigation. Neural Netw. 2002;15:689–707. doi: 10.1016/S0893-6080(02)00057-6. [DOI] [PubMed] [Google Scholar]
  • 28.Ji D, Dani JA. Inhibition and disinhibition of pyramidal neurons by activation of nicotinic receptors on hippocampal interneurons. J Neurophysiol. 2000;83:2682–2690. doi: 10.1152/jn.2000.83.5.2682. [DOI] [PubMed] [Google Scholar]
  • 29.Ji D, Lape R, Dani JA. Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity. Neuron. 2001;31:131–141. doi: 10.1016/S0896-6273(01)00332-4. [DOI] [PubMed] [Google Scholar]
  • 30.McGehee DS. Nicotinic receptors and hippocampal synaptic plasticity: it’s all in the timing. Trends Neurosci. 2002;25:171–172. doi: 10.1016/S0166-2236(00)02127-5. [DOI] [PubMed] [Google Scholar]
  • 31.Shao Z, Yakel JL. Single channel properties of neuronal nicotinic ACh receptors in stratum radiatum interneurons of rat hippocampal slices. J Physiol. 2000;527:507–513. doi: 10.1111/j.1469-7793.2000.00507.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.West KA, Brognard J, Clark AS, et al. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest. 2003;111:81–90. doi: 10.1172/JCI16147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Brunzell DH, Russell DS, Picciotto MR. In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57B1/6J mice. J Neurochem. 2003;84:1431–1441. doi: 10.1046/j.1471-4159.2003.01640.x. [DOI] [PubMed] [Google Scholar]
  • 34.Minana MD, Montoliu C, Llansola M, Grisolia S, Felipo V. Nicotine prevents glutamate-induced proteolysis of the microtubule-associated protein MAP-2 and glutamate neurotoxicity in primary cultures of cerebellar neurons. Neuropharmacology. 1998;37:847–857. doi: 10.1016/S0028-3908(98)00074-4. [DOI] [PubMed] [Google Scholar]
  • 35.Meyer EL, Gahring LC, Rogers SW. Nicotine preconditioning antagonizes activity-dependent caspase proteolysis of a glutamate receptor. J Biol Chem. 2002;277:10869–10875. doi: 10.1074/jbc.M106744200. [DOI] [PubMed] [Google Scholar]
  • 36.Oshikawa J, Toya Y, Fujita T, et al. Nicotinic acetylcholine receptor alpha7 regulates cAMP signal within lipid rafts. Am J Physiol Cell Physiol. 2003;285:C567–C574. doi: 10.1152/ajpcell.00422.2002. [DOI] [PubMed] [Google Scholar]
  • 37.Vallejo YF, Buisson B, Bertrand D, Green WN. Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J Neurosci. 2005;25:5563–5572. doi: 10.1523/JNEUROSCI.5240-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Xiao Y, Kellar KJ. The comparative pharmacology and up-regulation of rat neuronal nicotinic receptor subtype binding sites stably expressed in transfected mammalian cells. J Pharmacol Exp Ther. 2004;310:98–107. doi: 10.1124/jpet.104.066787. [DOI] [PubMed] [Google Scholar]
  • 39.Tapper AR, McKinney SL, Nashmi R, et al. Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science. 2004;306:1029–1032. doi: 10.1126/science.1099420. [DOI] [PubMed] [Google Scholar]
  • 40.Department of Health and Human Services. Nicotine: pharmacokinetics, metabolism and pharmacodynamics.The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General. 1988; Available at: http://www.cdc.gov/tobacco/sgr/sgr_1988/. Accessed January 6, 2006.
  • 41.Benowitz NL. Clinical pharmacology of nicotine. Annu Rev Med. 1986;37:21–32. doi: 10.1146/annurev.me.37.020186.000321. [DOI] [PubMed] [Google Scholar]
  • 42.Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003;9:125–134. [PMC free article] [PubMed] [Google Scholar]
  • 43.Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–388. doi: 10.1038/nature01339. [DOI] [PubMed] [Google Scholar]
  • 44.Wang H, Liao H, Ochani M, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10:1216–1221. doi: 10.1038/nm1124. [DOI] [PubMed] [Google Scholar]
  • 45.Wright SC, Zhong J, Zheng H, Larrick JW. Nicotine inhibition of apoptosis suggests a role in tumor promotion. FASEB J. 1993;7:1045–1051. [PubMed] [Google Scholar]
  • 46.Gahring LC, Carlson NG, Wieggel WA, Howard J, Rogers SW. Alcohol blocks TNFalpha but not other cytokine-mediated neuroprotection to NMDA. Alcohol Clin Exp Res. 1999;23:1571–1579. [PubMed] [Google Scholar]
  • 47.Coulie B, Camilleri M, Bharucha AE, Sandborn WJ, Burton D. Colonic motility in chronic ulcerative proctosigmoiditis and the effects of nicotine on colonic motility in patients and healthy subjects. Aliment Pharmacol Ther. 2001;15:653–663. doi: 10.1046/j.1365-2036.2001.00959.x. [DOI] [PubMed] [Google Scholar]
  • 48.McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2004;4:CD004722–CD004722. doi: 10.1002/14651858.CD004722.pub2. [DOI] [PubMed] [Google Scholar]
  • 49.Orr-Urtreger A, Kedmi M, Rosner S, Karmeli F, Rachmilewitz D. Increased severity of experimental colitis in alpha5 nicotinic acetylcholine receptor subunit-deficient mice. Neuroreport. 2005;16:1123–1127. doi: 10.1097/00001756-200507130-00018. [DOI] [PubMed] [Google Scholar]
  • 50.Glushakov AV, Voytenko LP, Skok MV, Skok V. Distribution of neuronal nicotinic acetylcholine receptors containing different alpha-subunits in the submucosal plexus of the guinea-pig. Auton Neurosci. 2004;110:19–26. doi: 10.1016/j.autneu.2003.08.012. [DOI] [PubMed] [Google Scholar]
  • 51.Richardson CE, Morgan JM, Jasani B, et al. Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the alpha3 nicotinic acetylcholine receptor subunit. Gastroenterology. 2001;121:350–357. doi: 10.1053/gast.2001.26320. [DOI] [PubMed] [Google Scholar]
  • 52.Xu W, Gelber S, Orr-Urtreger A, et al. Megacystis, mydriasis, and ion channel defect in mice lacking the alpha3 neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci USA. 1999;96:5746–5751. doi: 10.1073/pnas.96.10.5746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Zia S, Ndoye A, Nguyen VT, Grando SA. Nicotine enhances expression of the alpha3, alpha4, alpha5, and alpha7 nicotinic receptors modulating calcium metabolism and regulating adhesion and motility of respiratory epithelial cells. Res Commun Mol Pathol Pharmacol. 1997;97:243–262. [PubMed] [Google Scholar]
  • 54.Macklin KD, Maus AD, Pereira EF, Albuquerque EX, Conti-Fine BM. Human vascular endothelial cells express functional nicotinic acetylcholine receptors. J Pharmacol Exp Ther. 1998;287:435–439. [PubMed] [Google Scholar]
  • 55.Maus AD, Pereira EF, Karachunski PI, et al. Human and rodent bronchial epithelial cells express functional nicotinic acetylcholine receptors. Mol Pharmacol. 1998;54:779–788. doi: 10.1124/mol.54.5.779. [DOI] [PubMed] [Google Scholar]
  • 56.Plummer HK, Dhar M, Schuller HM. Expression of the alpha7 nicotinic acetylcholine receptor in human lung cells. Respir Res. 2005;6:29–29. doi: 10.1186/1465-9921-6-29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Reynolds PR, Hoidal JR. Temporal-spatial expression and transcriptional regulation of alpha7 nicotinic acetylcholine receptor (nAChR) by TTF-1 and EGR-1 during murine lung development. J Biol Chem. 2005;280:32548–32554. doi: 10.1074/jbc.M502231200. [DOI] [PubMed] [Google Scholar]
  • 58.Wang Y, Pereira EF, Maus AD, et al. Human bronchial epithelial and endothelial cells express alpha7 nicotinic acetylcholine receptors. Mol Pharmacol. 2001;60:1201–1209. doi: 10.1124/mol.60.6.1201. [DOI] [PubMed] [Google Scholar]
  • 59.Carlisle DL, Hopkins TM, Gaither-Davis A, et al. Nicotine signals through muscle-type and neuronal nicotinic acetylcholine receptors in both human bronchial epithelial cells and airway fibroblasts. Respir Res. 2004;5:27–27. doi: 10.1186/1465-9921-5-27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Albuquerque EX, Alkondon M, Pereira EF, et al. Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synaptic function. J Pharmacol Exp Ther. 1997;280:1117–1136. [PubMed] [Google Scholar]
  • 61.Mannino DM. Chronic obstructive pulmonary disease: definition and epidemiology. Respir Care. 2003;48:1185–1191. [PubMed] [Google Scholar]
  • 62.Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol. 2002;2:372–377. doi: 10.1038/nri803. [DOI] [PubMed] [Google Scholar]
  • 63.Sopori ML, Kozak W, Savage SM, Geng Y, Kluger MJ. Nicotine-induced modulation of T cell function: implications for inflammation and infection. Adv Exp Med Biol. 1998;437:279–289. doi: 10.1007/978-1-4615-5347-2_31. [DOI] [PubMed] [Google Scholar]
  • 64.Floto RA, Smith KG. The vagus nerve, macrophages, and nicotine. Lancet. 2003;361:1069–1070. doi: 10.1016/S0140-6736(03)12902-9. [DOI] [PubMed] [Google Scholar]
  • 65.Hance AJ, Basset F, Saumon G, et al. Smoking and interstitial lung disease: the effect of cigarette smoking on the incidence of pulmonary histiocytosis X and sarcoidosis. Ann N Y Acad Sci. 1986;465:643–656. doi: 10.1111/j.1749-6632.1986.tb18541.x. [DOI] [PubMed] [Google Scholar]
  • 66.Baur X, Richter G, Pethran A, Czuppon AB, Schwaiblmair M. Increased prevalence of IgG-induced sensitization and hypersensitivity pneumonitis (humidifier lung) in nonsmokers exposed to aerosols of a contaminated air conditioner. Respiration. 1992;59:211–214. doi: 10.1159/000196060. [DOI] [PubMed] [Google Scholar]
  • 67.Cornier Y, Gagnon L, Berube-Genest F, Fournier M. Sequential bronchoalveolar lavage in experimental extrinsic allergic alveolitis: the influence of cigarette smoking. Am Rev Respir Dis. 1988;137:1104–1109. doi: 10.1164/ajrccm/137.5.1104. [DOI] [PubMed] [Google Scholar]
  • 68.Marks MJ, Stitzel JA, Collins AC. Genetic influences on nicotine responses. Pharmacol Biochem Behav. 1989;33:667–678. doi: 10.1016/0091-3057(89)90406-1. [DOI] [PubMed] [Google Scholar]
  • 69.Gahring LC, Persiyanov K, Dunn D, Weiss R, Meyer EL, Rogers SW. Mouse strain-specific nicotinic acetylcholine receptor expression by inhibitory interneurons and astrocytes in the dorsal hippocampus. J Comp Neurol. 2004;468:334–346. doi: 10.1002/cne.10943. [DOI] [PubMed] [Google Scholar]
  • 70.Guerassimov A, Hoshino Y, Takubo Y, et al. The development of emphysema in cigarette smoke-exposed mice is strain dependent. Am J Respir Crit Care Med. 2004;170:974–980. doi: 10.1164/rccm.200309-1270OC. [DOI] [PubMed] [Google Scholar]
  • 71.Nakanishi N, Nakamura K, Matsuo Y, Suzuki K, Tatara K. Cigarette smoking and risk for impaired fasting glucose and type 2 diabetes in middle-aged Japanese men. Ann Intern Med. 2000;133:183–191. doi: 10.7326/0003-4819-133-3-200008010-00009. [DOI] [PubMed] [Google Scholar]
  • 72.Filozof C, Fernandez Pinilla MC, Fernandez-Cruz A. Smoking cessation and weight gain. Obes Rev. 2004;5:95–103. doi: 10.1111/j.1467-789X.2004.00131.x. [DOI] [PubMed] [Google Scholar]
  • 73.Miyazaki T, Shimada K, Mokuno H, Daida H. Adipocyte-derived plasma protein, adiponectin, is associated with smoking status in patients with coronary artery disease. Heart. 2003;89:663–663. doi: 10.1136/heart.89.6.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Liu RH, Mizuta M, Matsukura S. The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes. J Pharmacol Exp Ther. 2004;310:52–58. doi: 10.1124/jpet.103.065037. [DOI] [PubMed] [Google Scholar]
  • 75.Lindstrom JM. Acetylcholine receptors and myasthenia. Muscle Nerve. 2000;23:453–477. doi: 10.1002/(SICI)1097-4598(200004)23:4<453::AID-MUS3>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  • 76.Vincent A, Drachman DB. Myasthenia gravis. Adv Neurol. 2002;88:159–188. [PubMed] [Google Scholar]
  • 77.Navaneetham D, Penn A, Howard J, Conti-Fine BM. Expression of the alpha7 subunit of the nicotinic acetylcholine receptor in normal and myasthenic human thymuses. Cell Mol Biol (Noisy-le-grand) 1997;43:433–442. [PubMed] [Google Scholar]
  • 78.Vernino S, Low PA, Lennon VA. Experimental autoimmune autonomic neuropathy. J Neurophysiol. 2003;90:2053–2059. doi: 10.1152/jn.00408.2003. [DOI] [PubMed] [Google Scholar]
  • 79.Gahring L, Carlson NG, Meyer EL, Rogers SW. Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation. J Immunol. 2001;166:1433–1438. doi: 10.4049/jimmunol.166.3.1433. [DOI] [PubMed] [Google Scholar]
  • 80.Casciola-Rosen L, Andrade F, Ulanet D, Wong WB, Rosen A. Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity. J Exp Med. 1999;190:815–826. doi: 10.1084/jem.190.6.815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Gahring LC, Rogers SW. Autoimmunity to glutamate receptors in the central nervous system. Crit Rev Immunol. 2002;22:295–316. [PubMed] [Google Scholar]
  • 82.Lennon VA, Ermilov LG, Szurszewski JH, Vernino S. Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. J Clin Invest. 2003;111:907–913. doi: 10.1172/JCI17429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Mills CM. Cigarette smoking, cutaneous immunity, and inflammatory response. Clin Dermatol. 1998;16:589–594. doi: 10.1016/S0738-081X(98)00044-3. [DOI] [PubMed] [Google Scholar]
  • 84.Mihovilovic M, Denning S, Mai Y, et al. Thymocytes and cultured thymic epithelial cells express transcripts encoding alpha-3, alpha-5, and beta-4 subunits of neuronal nicotinic acetylcholine receptors. Preferential transcription of the alpha-3 and beta-4 genes by immature CD4+8+ thymocytes and evidence for response to nicotine in thymocytes. Ann N Y Acad Sci. 1998;841:388–392. doi: 10.1111/j.1749-6632.1998.tb10951.x. [DOI] [PubMed] [Google Scholar]
  • 85.Kawashima K, Fujii T. The lymphocytic cholinergic system and its biological function. Life Sci. 2003;72:2101–2109. doi: 10.1016/S0024-3205(03)00068-7. [DOI] [PubMed] [Google Scholar]
  • 86.Peng H, Ferris RL, Matthews T, Hiel H, Lopez-Albaitero A, Lustig LR. Characterization of the human nicotinic acetylcholine receptor subunit alpha (alpha) 9 (CHRNA9) and alpha (alpha) 10 (CHRNA 10) in lymphocytes. Life Sci. 2004;76:263–280. doi: 10.1016/j.lfs.2004.05.031. [DOI] [PubMed] [Google Scholar]
  • 87.Sopori ML, Kozak W. Immunomodulatory effects of cigarette smoke. J Neuroimmunol. 1998;83:148–156. doi: 10.1016/S0165-5728(97)00231-2. [DOI] [PubMed] [Google Scholar]
  • 88.Kalra R, Singh SP, Savage SM, Finch GL, Sopori ML. Effects of cigarette smoke on immune response: chronic exposure to cigarette smoke impairs antigen-mediated signaling in T cells and deplets IP3-sensitive Ca(2+) stores. J Pharmacol Exp Ther. 2000;293:166–171. [PubMed] [Google Scholar]
  • 89.van Dijk AP, Meijssen MA, Brouwer AJ, et al. Transdermal nicotine inhibits interleukin 2 systhesis by mononuclear cells derived from healthy volunteers. Eur J Clin Invest. 1998;28:664–671. doi: 10.1046/j.1365-2362.1998.00344.x. [DOI] [PubMed] [Google Scholar]
  • 90.Nuorti JP, Butler JC, Farley MM, et al. Cigarette smoking and invasive pneum ococcal disease. Active Bacterial Core Surveillance Team. N Engl J Med. 2000;342:681–689. doi: 10.1056/NEJM200003093421002. [DOI] [PubMed] [Google Scholar]
  • 91.Matsunaga K, Klein TW, Friedman H, Yamamoto Y. Involvement of nicotinic acetylcholine receptors in suppression of antimicrobial activity and cytokine responses of alveolar macrophages to Legionella pneumophila infection by nicotine. J Immunol. 2001;167:6518–6524. doi: 10.4049/jimmunol.167.11.6518. [DOI] [PubMed] [Google Scholar]
  • 92.Blanchet MR, Israel-Assayag E, Cormier Y. Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med. 2004;169:903–909. doi: 10.1164/rccm.200210-1154OC. [DOI] [PubMed] [Google Scholar]
  • 93.Shivji M, Burger S, Moncada CA, Clarkson AB, Merali S. Effect of nicotine on lung S-adenosylmethionine and development ofPneumocystis pneumonia. J Biol Chem. 2005;280:15219–15228. doi: 10.1074/jbc.M413946200. [DOI] [PubMed] [Google Scholar]
  • 94.Saah AJ, Hoover DR, Peng Y, et al. Predictors for failure ofPneumocystis carinii pneumonia prophylaxis. Multicenter AIDS Cohort Study. JAMA. 1995;273:1197–1202. doi: 10.1001/jama.273.15.1197. [DOI] [PubMed] [Google Scholar]
  • 95.Aicher A, Heeschen C, Mohaupt M, Cooke JP, Zeiher AM, Dimmeler S. Nicotine strongly activates dendritic cell-mediated adaptive immunity: potential role for progression of atherosclerotic lesions. Circulation. 2003;107:604–611. doi: 10.1161/01.CIR.0000047279.42427.6D. [DOI] [PubMed] [Google Scholar]
  • 96.Kadunce DP, Burr R, Gress R, Kanner R, Lyon JL, Zone JJ. Cigarette smoking: risk factor for premature facial wrinkling. Ann Intern Med. 1991;114:840–844. doi: 10.7326/0003-4819-114-10-840. [DOI] [PubMed] [Google Scholar]
  • 97.Misery L. Nicotine effects on skin: are they positive or negative? Exp Dermatol. 2004;13:665–670. doi: 10.1111/j.0906-6705.2004.00274.x. [DOI] [PubMed] [Google Scholar]
  • 98.Grando SA. Biological functions of keratinocyte cholinergic receptors. J Investig Dermatol Symp Proc. 1997;2:41–48. doi: 10.1038/jidsymp.1997.10. [DOI] [PubMed] [Google Scholar]
  • 99.Kurzen H, Berger H, Jager C, et al. Phenotypical and molecular profiling of the extraneuronal cholinergic system of the skin. J Invest Dermatol. 2004;123:937–949. doi: 10.1111/j.0022-202X.2004.23425.x. [DOI] [PubMed] [Google Scholar]
  • 100.Zia S, Ndoye A, Lee TX, Webber RJ, Grando SA. Receptormediated inhibition of keratinocyte migration by nicotine involves modulations of calcium influx and intracellular concentration. J Pharmacol Exp Ther. 2000;293:973–981. [PubMed] [Google Scholar]
  • 101.Chernyavsky AI, Arredondo J, Marubio LM, Grando SA. Differential regulation of keratinocyte chemokinesis and chemotaxis through distinct nicotinic receptor subtypes. J Cell Sci. 2004;117:5665–5679. doi: 10.1242/jcs.01492. [DOI] [PubMed] [Google Scholar]
  • 102.Arredondo J, Nguyen VT, Chernyavsky AI, et al. Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium. J Cell Biol. 2002;159:325–336. doi: 10.1083/jcb.200206096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Arredondo J, Nguyen VT, Chernyavsky AI, et al. Functional role of alpha7 nicotinic receptor in physiological control of cutaneous homeostasis. Life Sci. 2003;72:2063–2067. doi: 10.1016/S0024-3205(03)00084-5. [DOI] [PubMed] [Google Scholar]
  • 104.Zwart R, Van Kleef RG, Vijverberg HP. Physostigmine and atropine potentiate and inhibit, neuronal alpha4 beta4 nicotinic receptors. Ann N Y Acad Sci. 1999;868:636–639. doi: 10.1111/j.1749-6632.1999.tb11339.x. [DOI] [PubMed] [Google Scholar]
  • 105.Bergstrom J. Tobacco smoking and chronic destructive periodontal disease. Odontology. 2004;92:1–8. doi: 10.1007/s10266-004-0043-4. [DOI] [PubMed] [Google Scholar]
  • 106.Wendell KJ, Stein SH. Regulation of cytokine production in human gingival fibroblasts following treatment with nicotine and lipopolysaccharide. J Periodontol. 2001;72:1038–1044. doi: 10.1902/jop.2001.72.8.1038. [DOI] [PubMed] [Google Scholar]
  • 107.Arredondo J, Chernyavsky AI, Marubio LM, et al. Receptormediated tobacco toxicity: regulation of gene expression through alpha3beta2 nicotinic receptor in oral epithelial cells. Am J Pathol. 2005;166:597–613. doi: 10.1016/s0002-9440(10)62281-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Heeschen C, Jang JJ, Weis M, et al. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 2001;7:833–839. doi: 10.1038/89961. [DOI] [PubMed] [Google Scholar]
  • 109.Di Luozzo G, Pradhan S, Dhadwal AK, Chen A, Ueno H, Sumpio BE. Nicotine induces mitogen-activated protein kinase-dependent vascular smooth muscle cell migration. Atherosclerosis. 2005;178:271–277. doi: 10.1016/j.atherosclerosis.2004.09.017. [DOI] [PubMed] [Google Scholar]
  • 110.Moccia F, Frost C, Berra-Romani R, Tanzi F, Adams DJ. Expression and function of neuronal nicotinic ACh receptors in rat microvascular endothelial cells. Am J Physiol Heart Circ Physiol. 2004;286:H486–H491. doi: 10.1152/ajpheart.00620.2003. [DOI] [PubMed] [Google Scholar]
  • 111.Saeed RW, Varma S, Peng-Nemeroff T, et al. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J Exp Med. 2005;201:1113–1123. doi: 10.1084/jem.20040463. [DOI] [PMC free article] [PubMed] [Google Scholar]

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