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Author (up) Albuquerque, E.X.; Pereira, E.F.R.; Alkondon, M.; Rogers, S.W. file  url
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  Title Mammalian nicotinic acetylcholine receptors: from structure to function Type Journal Article
  Year 2009 Publication Physiological Reviews Abbreviated Journal Physiol Rev  
  Volume 89 Issue 1 Pages 73-120  
  Keywords Alzheimer Disease/physiopathology; Animals; Brain/physiology; Disease Models, Animal; Gene Expression Regulation/physiology; Humans; Parkinson Disease/physiopathology; Receptors, Nicotinic/*chemistry/*physiology  
  Abstract The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.  
  Call Number Serial 1876  
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Author (up) Arias, H.R. file  url
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  Title Positive and negative modulation of nicotinic receptors Type Journal Article
  Year 2010 Publication Advances in Protein Chemistry and Structural Biology Abbreviated Journal Adv Protein Chem Struct Biol  
  Volume 80 Issue Pages 153-203  
  Keywords Acetylcholine/chemistry/physiology; Allosteric Regulation; Allosteric Site/genetics; Animals; Cholinergic Antagonists/*pharmacology/therapeutic use; Crystallography, X-Ray; Humans; Ion Channel Gating/drug effects; Mice; Nicotinic Agonists/*pharmacology/therapeutic use; Protein Structure, Tertiary; Receptors, Nicotinic/*chemistry/*physiology; Structure-Activity Relationship  
  Abstract Nicotinic acetylcholine receptors (AChRs) are one of the best characterized ion channels from the Cys-loop receptor superfamily. The study of acetylcholine binding proteins and prokaryotic ion channels from different species has been paramount for the understanding of the structure-function relationship of the Cys-loop receptor superfamily. AChR function can be modulated by different ligand types. The neurotransmitter ACh and other agonists trigger conformational changes in the receptor, finally opening the intrinsic cation channel. The so-called gating process couples ligand binding, located at the extracellular portion, to the opening of the ion channel, located at the transmembrane region. After agonist activation, in the prolonged presence of agonists, the AChR becomes desensitized. Competitive antagonists overlap the agonist-binding sites inhibiting the pharmacological action of agonists. Positive allosteric modulators (PAMs) do not bind to the orthostetic binding sites but allosterically enhance the activity elicited by agonists by increasing the gating process (type I) and/or by decreasing desensitization (type II). Instead, negative allosteric modulators (NAMs) produce the opposite effects. Interestingly, this negative effect is similar to that found for another class of allosteric drugs, that is, noncompetitive antagonists (NCAs). However, the main difference between both categories of drugs is based on their distinct binding site locations. Although both NAMs and NCAs do not bind to the agonist sites, NACs bind to sites located in the ion channel, whereas NAMs bind to nonluminal sites. However, this classification is less clear for NAMs interacting at the extracellular-transmembrane interface where the ion channel mouth might be involved. Interestingly, PAMs and NAMs might be developed as potential medications for the treatment of several diseases involving AChRs, including dementia-, skin-, and immunological-related diseases, drug addiction, and cancer. More exciting is the potential combination of specific agonists with specific PAMs. However, we are still in the beginning of understanding how these compounds act and how these drugs can be used therapeutically.  
  Call Number Serial 1886  
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