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Neuronal Nicotinic Receptors: from Structure to Pathology

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Neuronal Nicotinic Receptors: from Structure to Pathology Progress in Neurobiology 74 (2004) 363–396 www.elsevier.com/locate/pneurobio Neuronal nicotinic receptors: from structure to pathology C. Gotti, F. Clementi* CNR, Institute of Neuroscience, Cellular and Molecular Pharmacology Section, Department of Medical Pharmacology and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy Received 22 July 2004; accepted 29 September 2004 Available online 27 October 2004 Abstract Neuronal nicotinic receptors (NAChRs) form a heterogeneous family of ion channels that are differently expressed in many regions of the central nervous system (CNS) and peripheral nervous system. These different receptor subtypes, which have characteristic pharmacological and biophysical properties, have a pentameric structure consisting of the homomeric or heteromeric combination of 12 different subunits (a2–a10, b2–b4). By responding to the endogenous neurotransmitter acetylcholine, NAChRs contribute to a wide range of brain activities and influence a number of physiological functions. Furthermore, it is becoming evident that the perturbation of cholinergic nicotinic neurotransmission can lead to various diseases involving nAChR dysfunction during development, adulthood and ageing. In recent years, it has been discovered that NAChRs are present in a number of non-neuronal cells where they play a significant functional role and are the pathogenetic targets in several diseases. NAChRs are also the target of natural ligands and toxins including nicotine (Nic), the most widespread drug of abuse. This review will attempt to survey the major achievements reached in the study of the structure and function of NAChRs by examining their regional and cellular localisation and the molecular basis of their functional diversity mainly in pharmacological and biochemical terms. The recent availability of mice with the genetic ablation of single or double nicotinic subunits or point mutations have shed light on the role of nAChRs in major physiological functions, and we will here discuss recent data relating to their behavioural phenotypes. Finally, the role of NAChRs in disease will be considered in some details. # 2004 Elsevier Ltd. All rights reserved. Contents 1. Introduction . ............................................................................. 365 1.1. Molecular structure of NAChRs ............................................................ 365 1.1.1. Two classes of NAChRs . ........................................................ 365 1.1.2. The ligand binding sites . ........................................................ 365 1.1.3. NAChR transition states . ........................................................ 366 1.2. aBgtx-nAChRs . ..................................................................... 366 1.2.1. Homomeric or heteromeric receptors?. ................................................ 367 1.2.2. Calcium permeability . ............................................................ 367 Abbreviations: Abs, polyclonal antibodies; b-AP, b-amyloid protein; aBgtx, aBungarotoxin; aBgtx-nAChRs, aBgtx-sensitive neuronal nicotinic receptors; 6OHDA, 6 hydroxydopamine; ACh, acetylcholine; AChE, acetylcholinesterase; AD, Alzheimer’s disease; ADHD, attention deficit hyperactivity disorder; ADNFLE, autosomal dominant frontal lobe epilepsy; CNS, central nervous system; aCntxMII, aconotoxin MII; DA, dopamine; dLGL, dorso lateral geniculate nucleus; Epi, epibatidine; Kin, knock in; Ko, knock out; LPS, endotoxin polysaccaride; MLA, methyllycaconitine; NA, noradrenaline; nAChRs, non aBgtx-sensitive neuronal nicotinic receptors; NAChRs, neuronal nicotinic receptors; Nic, nicotine; PD, Parkinson’s disease; PET, positron emission tomography; SCG, superior cervical ganglion; SCLC, small-cell lung carcinoma; SHR, spontaneously hypertensive rats; VOCCS, voltage operated calcium channels; VTA, ventral tegmental area; WT, wildtype * Corresponding author. Tel.: +39 02 50316962; fax: +39 02 7490574. E-mail address: [email protected] (F. Clementi). 0301-0082/$ – see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2004.09.006 364 C. Gotti, F. Clementi / Progress in Neurobiology 74 (2004) 363–396 1.3. nAChRs . ........................................................................... 367 1.3.1. Receptor stoichiometry . .......................................................... 367 1.3.2. The role of a5 and b3 subunits ...................................................... 368 1.3.3. nAChR and calcium homeostasis . .................................................. 368 2. NAChR localisation . ....................................................................... 368 2.1. Brain cholinergic system . .............................................................. 368 2.2. Methods of study . ................................................................... 369 2.3. Brain localisation of NAChRs . .......................................................... 370 2.3.1. Rodent distribution . .............................................................. 370 2.3.2. nAChRs in retina . .............................................................. 370 2.3.3. nAChRs in striatum .............................................................. 371 2.3.4. Primate distribution .............................................................. 371 2.4. Pre- or postsynaptic distribution? . .......................................................... 372 2.5. Specificity of primate nAChR distribution . .................................................. 374 3. Changes during development and aging . .......................................................... 374 3.1. nAChRs . ........................................................................... 375 3.2. aBgtx-nAChRs ....................................................................... 375 3.3. Relevance of NACHRs during ageing . ...................................................... 375 4. Non-neuronal localisations of NAChRs. .......................................................... 376 4.1. Muscle . ........................................................................... 376 4.2. Lymphoid tissue ....................................................................... 376 4.3. Macrophages . ....................................................................... 376 4.4. Skin ............................................................................... 377 4.5. Lung cells ........................................................................... 377 4.6. Vascular tissue . ....................................................................... 377 4.7. Astrocytes ........................................................................... 377 5. Studies of knock out and knock in mice . .......................................................... 378 5.1. Phenotype of a3, a5, b4 Ko and b2–b4 double Ko mice .......................................... 378 5.2. Phenotype of a4 Ko and Kin mice .......................................................... 378 5.3. Phenotype of b2 Ko mice . .............................................................. 378 5.3.1. Learning, memory and neuroprotection . .............................................. 379 5.3.2. Drug reinforcement. .............................................................. 379 5.3.3. Development of the nervous system . .................................................. 380 5.3.4. Organisation of sleep . .......................................................... 380 5.4. Phenotype of a6 and b3 Ko mice .......................................................... 380 5.5. Phenotype of a7 Ko mice . .............................................................. 381 5.6. Phenotype of a9 Ko mice . .............................................................. 382 5.7. Conclusions . ....................................................................... 382 6. NAChRs in pathology ....................................................................... 382 6.1. Diseases affecting the nervous system. ...................................................... 382 6.1.1. Age dependent disorders . .......................................................... 382 6.1.2. Age-independent disorders.......................................................... 383 6.1.3. Age-related degenerative diseases of the brain . .......................................... 383 6.2. Pathologies in non-neuronal tissues and cells. .................................................. 385 6.2.1. Lung cells . ................................................................... 385 6.3. Vascular smooth muscle and endothelial cells .................................................. 385 6.4. Dysautonomia and blood pressure control . .................................................. 386 6.5. Intestinal epithelium . ................................................................... 386 7. Conclusions and perspectives .................................................................. 386 Acknowledgements . ........................................................................... 387 References................................................................................... 387 C. Gotti, F. Clementi / Progress in Neurobiology 74 (2004) 363–396 365 1. Introduction prototype), which also includes gamma aminobutyric acid (GABAA and GABAC), glycine and 5-hydroxytryptamine The cholinergic system is one of the most important and (5-HT3) receptors (reviewed in Changeux and Edelstein, filogenetically oldest
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