Neuropharmacology 96 (2015) 135e136
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Editorial
The nicotinic acetylcholine receptor: From molecular biology to cognition
This Special Issue of Neuropharmacology is dedicated to nicotinic acetylcholine receptors (nAChR) signaling from molecular biology to cognition and to their contribution to health and diseases with a special emphasis on drug design. It regroups contributions from a broad diversity of eminent specialists which illustrate the large range of topics covered by the research on nAChRs. Moreover the nAChR has, for decades, taken a highly emblematic position in receptor research. Historically two main figures have been considered as the founding fathers of receptor theory. Paul Ehrlich in an attempt to explain the origin of serum antibodies, proposed, in 1897, that cells contains special structures which he called ‘side-chain’ receptors, that could react with infectious agents and inactivate them. Closer to our interest, the neuro-pharmacologist John-Newport Langley in his pioneering studies on “the reaction of striated muscle to nicotine and to curare” proposed that “the muscle substance which combines with nicotine and curare is not identical with the substance which contracts … I have called it the receptive substance” (1906) and he further added the important feature that “it is localized under the nerve terminal” (1907). Langley's definition of the concept of pharmacological receptor was thus grounded on the properties of the nAChR from the neuromuscular junction. It is thus not too surprising that the first attempts to biochemically identify a neurotransmitter receptor were carried out with Langley's nAChR. After many failures, mainly due to the lack of specificity of the ligands used and to the small quantities present in the brain tissue used, the receptive substance had remained a mysterious entity for about 65 years. It was not until the joint use of snake toxins, as highly selective and almost irreversible ligands, and of a very rich source of muscle type nAChR in the electric organ of fish resulted in 1970 in its identification as a defined protein species. Another historically symbolic feature of the nAChR is that, very early on, even before its identification, the nAChR was hypothesized to behave as an allosteric protein, according to the scheme initially postulated with bacterial regulatory enzymes. Decades of biochemical and biophysical research demonstrated the general validity of the concept, yet with aspects related to its integration to the membrane and its role in inter-cellular communication. Research on the nAChR also pioneered the discovery and development of a new class of pharmacological agents referred to as allosteric modulators, characterized by the fact that they bind to sites topographically distinct from the ACh binding sites and the ion channel. This Special Issue shows that, today, the research on nAChR is very diverse, progresses rapidly and results in multiple medical applications including among many others nicotine addiction and cognitive enhancement. http://dx.doi.org/10.1016/j.neuropharm.2015.03.024 0028-3908/© 2015 Elsevier Ltd. All rights reserved.
At the molecular level, cutting-edge advances in the X-ray crystallography and molecular dynamics of bacterial and eukaryotic orthologs of nicotinic receptors reviewed by Cecchini and Changeux (2015) has lead to the proposal of an allosteric mechanism for activation at the atomic level, whilst models of desensitization are mostly based on molecular dynamics simulations. Combined with high resolution electrophysiological recordings, these molecular processes have profoundly changed the field as presented by Auerbach (2015). His extensive mutational analysis of the muscle nAChR reveals the energy at work within the tridimensional structure during the activation process within the framework of a two-state Monod-WymaneChangeux model. Two reviews then summarize the allosteric modulation of nault et al. nAChRs by membrane components and solutes. He (2015) focus on proteinelipid interactions and their consequence on the allosteric transitions, while Forman et al. (2015) present the recent advance in the identification of allosteric binding sites for general anesthetics, which effects, in humans, are partly mediated by nicotinic receptors. nAChR are further studied in their cellular context by Henderson and Lester (2015) who summarize the complex inside-out pharmacology of nicotinic compounds that up-regulate nAChR number in intracellular organelles and promote their forward trafficking. Last, Wang et al. (2015) summarize the progresses in the identification of alpha6-containing nAChR that play an important role in nicotine addiction. An important facet of nAChR studies, which have made major progress over the past years, has been the precise elucidation of the role of neuronal nAChRs in brain physiology and pathology. Several reviews here highlight discoveries made with rodent models, several others describe work done in humans and primates though genetics, functional imaging of higher brain functions, and neurodegeneration. Using rodent models, Wilking and Stitzel (2015) apply gene targeting to study genetic polymorphisms and review what is known about nAChR subunit variation in mice and how it relates to changes in nAChR expression and function in the brain. Several reviews deal with the modeling of human brain phenotypes, essentially pathological ones, which are associated with nicotinic receptors using mice models. Antolin-Fontes et al. (2015) focus on nicotine withdrawal and aversion, and describe the habenulo-interpeduncular (Hb-IPN) midbrain pathway that has re-emerged as a new critical crossroad that influences the brain response to nicotine. Jackson et al. (2015) further discuss recent evidence examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Their research has already identified an important role for nicotinic receptor subtypes in different aspects of the nicotine
136
Editorial / Neuropharmacology 96 (2015) 135e136
withdrawal syndrome, such as physical or affective signs. Picciotto et al. (2015) review their finding on the role of nAChRs in regulating mood and anxiety, and on the closely related construct of aggression-related behavioral states. They suggest avenues for future study to identify how nAChRs and nicotinic agents may et al. (2015) play a role in these clinically important areas. Naude provide an update for the role of nicotine, acetylcholine and nAChRs on decision-making processes, with an emphasis on impulsivity and risk-taking. Lombardo and Maskos (2015) conclude the section on mouse models with a summary of the role of nAChRs in Alzheimer's disease pathology and potential treatments. Moving to higher order brain models, Shorey-Kendrick et al. (2015) give a comprehensive overview of genetic polymorphisms of nAChR genes in primates, and their functional consequences. Focusing on humans, Sinkus et al. (2015) describe their in-depth characterization of human genetic and functional studies of a partial duplication of the CHRNA7 gene specific to humans, and its implication in disease. This is followed up by a discussion of emerging findings of functional imaging studies in humans that increasingly link nAChR genotype to brain phenotype (Nees, 2015). Finally, Zoli et al. (2015) usefully compare the regional distribution of the homologous nAChRs in the primate and human brain. In conclusion, nAChR studies are still on the forefront of receptor research and offer general models on the structural dynamics of receptor activation, of receptor-based diseases and of drug design far beyond the field of acetylcholine nicotinic receptors. References €rlich, A., Iban ~ ez-Tallon, I., 2015. The HabenuloAntolin-Fontes, B., Ables, J.L., Go Interpeduncular pathway in nicotine aversion and withdrawal. Neuropharmacology 96, 213e222. Auerbach, A., 2015. Agonist activation of a nicotinic acetylcholine receptor. Neuropharmacology 96, 150e156. Cecchini, M., Changeux, J.-P., 2015. The nicotinic acetylcholine receptor and its prokaryotic Homologues: structure, conformational transitions & allosteric modulation. Neuropharmacology 96, 137e149.
Forman, S.A., Chiara, D.C., Miller, K.W., 2015. Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors. Neuropharmacology 96, 169e177. nault, C.M., Sun, J., Daniel Therien, J.P., daCosta, C.J.B., Carswell, C.L., Labriola, J.M., He Juranka, P.J., Baenziger, J.E., 2015. The role of the M4 lipid-sensor in the folding, trafficking, and allosteric modulation of nicotinic acetylcholine receptors. Neuropharmacology 96, 157e168. Henderson, Brandon J., Lester, H.A., 2015. Inside-out neuropharmacology of nicotinic drugs. Neuropharmacology 96, 178e193. Jackson, K.J., Muldoon, P.P., De Biasi, M., Damaj, M.I., 2015. New mechanisms and perspectives in nicotine withdrawal. Neuropharmacology 96, 223e234. Lombardo, S., Maskos, U., 2015. Role of the nicotinic acetylcholine receptor in Alzheimer's Disease pathology and treatment. Neuropharmacology 96, 255e262. , J., Dongelmans, M., Faure, P., 2015. Nicotinic alteration of decision-making. Naude Neuropharmacology 96, 244e254. Nees, F., 2015. The nicotinic cholinergic system function in the human brain. Neuropharmacology 96, 289e301. Picciotto, M.R., Lewis, A.L., van Schalkwyk, G.I., Mineur, Y.S., 2015. Mood and anxiety regulation by nicotinic acetylcholine receptors: a potential pathway to modulate aggression and related behavioral states. Neuropharmacology 96, 235e243. Shorey-Kendrick, L.E., Ford, M.M., Allen, D.C., Kuryatov, A., Lindstrom, J., Wilhelm, L., Grant, K.A., Spindel, E.R., 2015. Nicotinic receptors in non-human primates: analysis of genetic and functional conservation with humans. Neuropharmacology 96, 263e273. Sinkus, M.L., Graw, S., Freedman, R., Ross, R.G., Lester, H.A., Leonard, S., 2015. The human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation, and function. Neuropharmacology 96, 274e288. Wang, J., Kuryatov, A., Lindstrom, J., 2015. Expression of cloned a6* nicotinic acetylcholine receptors. Neuropharmacology 96, 194e204. Wilking, J.A., Stitzel, J.A., 2015. Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: consequences and confounds. Neuropharmacology 96, 205e212. Zoli, M., Pistillo, F., Gotti, C., 2015. Diversity of native nicotinic receptor subtypes in mammalian brain. Neuropharmacology 96, 302e311.
Jean-Pierre Changeux*, Pierre-Jean Corringer, Uwe Maskos Institut Pasteur, Paris, France *
Corresponding author. E-mail address: [email protected] (J.-P. Changeux). Available online 1 April 2015
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Editorial
The nicotinic acetylcholine receptor: From molecular biology to cognition
This Special Issue of Neuropharmacology is dedicated to nicotinic acetylcholine receptors (nAChR) signaling from molecular biology to cognition and to their contribution to health and diseases with a special emphasis on drug design. It regroups contributions from a broad diversity of eminent specialists which illustrate the large range of topics covered by the research on nAChRs. Moreover the nAChR has, for decades, taken a highly emblematic position in receptor research. Historically two main figures have been considered as the founding fathers of receptor theory. Paul Ehrlich in an attempt to explain the origin of serum antibodies, proposed, in 1897, that cells contains special structures which he called ‘side-chain’ receptors, that could react with infectious agents and inactivate them. Closer to our interest, the neuro-pharmacologist John-Newport Langley in his pioneering studies on “the reaction of striated muscle to nicotine and to curare” proposed that “the muscle substance which combines with nicotine and curare is not identical with the substance which contracts … I have called it the receptive substance” (1906) and he further added the important feature that “it is localized under the nerve terminal” (1907). Langley's definition of the concept of pharmacological receptor was thus grounded on the properties of the nAChR from the neuromuscular junction. It is thus not too surprising that the first attempts to biochemically identify a neurotransmitter receptor were carried out with Langley's nAChR. After many failures, mainly due to the lack of specificity of the ligands used and to the small quantities present in the brain tissue used, the receptive substance had remained a mysterious entity for about 65 years. It was not until the joint use of snake toxins, as highly selective and almost irreversible ligands, and of a very rich source of muscle type nAChR in the electric organ of fish resulted in 1970 in its identification as a defined protein species. Another historically symbolic feature of the nAChR is that, very early on, even before its identification, the nAChR was hypothesized to behave as an allosteric protein, according to the scheme initially postulated with bacterial regulatory enzymes. Decades of biochemical and biophysical research demonstrated the general validity of the concept, yet with aspects related to its integration to the membrane and its role in inter-cellular communication. Research on the nAChR also pioneered the discovery and development of a new class of pharmacological agents referred to as allosteric modulators, characterized by the fact that they bind to sites topographically distinct from the ACh binding sites and the ion channel. This Special Issue shows that, today, the research on nAChR is very diverse, progresses rapidly and results in multiple medical applications including among many others nicotine addiction and cognitive enhancement. http://dx.doi.org/10.1016/j.neuropharm.2015.03.024 0028-3908/© 2015 Elsevier Ltd. All rights reserved.
At the molecular level, cutting-edge advances in the X-ray crystallography and molecular dynamics of bacterial and eukaryotic orthologs of nicotinic receptors reviewed by Cecchini and Changeux (2015) has lead to the proposal of an allosteric mechanism for activation at the atomic level, whilst models of desensitization are mostly based on molecular dynamics simulations. Combined with high resolution electrophysiological recordings, these molecular processes have profoundly changed the field as presented by Auerbach (2015). His extensive mutational analysis of the muscle nAChR reveals the energy at work within the tridimensional structure during the activation process within the framework of a two-state Monod-WymaneChangeux model. Two reviews then summarize the allosteric modulation of nault et al. nAChRs by membrane components and solutes. He (2015) focus on proteinelipid interactions and their consequence on the allosteric transitions, while Forman et al. (2015) present the recent advance in the identification of allosteric binding sites for general anesthetics, which effects, in humans, are partly mediated by nicotinic receptors. nAChR are further studied in their cellular context by Henderson and Lester (2015) who summarize the complex inside-out pharmacology of nicotinic compounds that up-regulate nAChR number in intracellular organelles and promote their forward trafficking. Last, Wang et al. (2015) summarize the progresses in the identification of alpha6-containing nAChR that play an important role in nicotine addiction. An important facet of nAChR studies, which have made major progress over the past years, has been the precise elucidation of the role of neuronal nAChRs in brain physiology and pathology. Several reviews here highlight discoveries made with rodent models, several others describe work done in humans and primates though genetics, functional imaging of higher brain functions, and neurodegeneration. Using rodent models, Wilking and Stitzel (2015) apply gene targeting to study genetic polymorphisms and review what is known about nAChR subunit variation in mice and how it relates to changes in nAChR expression and function in the brain. Several reviews deal with the modeling of human brain phenotypes, essentially pathological ones, which are associated with nicotinic receptors using mice models. Antolin-Fontes et al. (2015) focus on nicotine withdrawal and aversion, and describe the habenulo-interpeduncular (Hb-IPN) midbrain pathway that has re-emerged as a new critical crossroad that influences the brain response to nicotine. Jackson et al. (2015) further discuss recent evidence examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Their research has already identified an important role for nicotinic receptor subtypes in different aspects of the nicotine
136
Editorial / Neuropharmacology 96 (2015) 135e136
withdrawal syndrome, such as physical or affective signs. Picciotto et al. (2015) review their finding on the role of nAChRs in regulating mood and anxiety, and on the closely related construct of aggression-related behavioral states. They suggest avenues for future study to identify how nAChRs and nicotinic agents may et al. (2015) play a role in these clinically important areas. Naude provide an update for the role of nicotine, acetylcholine and nAChRs on decision-making processes, with an emphasis on impulsivity and risk-taking. Lombardo and Maskos (2015) conclude the section on mouse models with a summary of the role of nAChRs in Alzheimer's disease pathology and potential treatments. Moving to higher order brain models, Shorey-Kendrick et al. (2015) give a comprehensive overview of genetic polymorphisms of nAChR genes in primates, and their functional consequences. Focusing on humans, Sinkus et al. (2015) describe their in-depth characterization of human genetic and functional studies of a partial duplication of the CHRNA7 gene specific to humans, and its implication in disease. This is followed up by a discussion of emerging findings of functional imaging studies in humans that increasingly link nAChR genotype to brain phenotype (Nees, 2015). Finally, Zoli et al. (2015) usefully compare the regional distribution of the homologous nAChRs in the primate and human brain. In conclusion, nAChR studies are still on the forefront of receptor research and offer general models on the structural dynamics of receptor activation, of receptor-based diseases and of drug design far beyond the field of acetylcholine nicotinic receptors. References €rlich, A., Iban ~ ez-Tallon, I., 2015. The HabenuloAntolin-Fontes, B., Ables, J.L., Go Interpeduncular pathway in nicotine aversion and withdrawal. Neuropharmacology 96, 213e222. Auerbach, A., 2015. Agonist activation of a nicotinic acetylcholine receptor. Neuropharmacology 96, 150e156. Cecchini, M., Changeux, J.-P., 2015. The nicotinic acetylcholine receptor and its prokaryotic Homologues: structure, conformational transitions & allosteric modulation. Neuropharmacology 96, 137e149.
Forman, S.A., Chiara, D.C., Miller, K.W., 2015. Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors. Neuropharmacology 96, 169e177. nault, C.M., Sun, J., Daniel Therien, J.P., daCosta, C.J.B., Carswell, C.L., Labriola, J.M., He Juranka, P.J., Baenziger, J.E., 2015. The role of the M4 lipid-sensor in the folding, trafficking, and allosteric modulation of nicotinic acetylcholine receptors. Neuropharmacology 96, 157e168. Henderson, Brandon J., Lester, H.A., 2015. Inside-out neuropharmacology of nicotinic drugs. Neuropharmacology 96, 178e193. Jackson, K.J., Muldoon, P.P., De Biasi, M., Damaj, M.I., 2015. New mechanisms and perspectives in nicotine withdrawal. Neuropharmacology 96, 223e234. Lombardo, S., Maskos, U., 2015. Role of the nicotinic acetylcholine receptor in Alzheimer's Disease pathology and treatment. Neuropharmacology 96, 255e262. , J., Dongelmans, M., Faure, P., 2015. Nicotinic alteration of decision-making. Naude Neuropharmacology 96, 244e254. Nees, F., 2015. The nicotinic cholinergic system function in the human brain. Neuropharmacology 96, 289e301. Picciotto, M.R., Lewis, A.L., van Schalkwyk, G.I., Mineur, Y.S., 2015. Mood and anxiety regulation by nicotinic acetylcholine receptors: a potential pathway to modulate aggression and related behavioral states. Neuropharmacology 96, 235e243. Shorey-Kendrick, L.E., Ford, M.M., Allen, D.C., Kuryatov, A., Lindstrom, J., Wilhelm, L., Grant, K.A., Spindel, E.R., 2015. Nicotinic receptors in non-human primates: analysis of genetic and functional conservation with humans. Neuropharmacology 96, 263e273. Sinkus, M.L., Graw, S., Freedman, R., Ross, R.G., Lester, H.A., Leonard, S., 2015. The human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation, and function. Neuropharmacology 96, 274e288. Wang, J., Kuryatov, A., Lindstrom, J., 2015. Expression of cloned a6* nicotinic acetylcholine receptors. Neuropharmacology 96, 194e204. Wilking, J.A., Stitzel, J.A., 2015. Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: consequences and confounds. Neuropharmacology 96, 205e212. Zoli, M., Pistillo, F., Gotti, C., 2015. Diversity of native nicotinic receptor subtypes in mammalian brain. Neuropharmacology 96, 302e311.
Jean-Pierre Changeux*, Pierre-Jean Corringer, Uwe Maskos Institut Pasteur, Paris, France *
Corresponding author. E-mail address: [email protected] (J.-P. Changeux). Available online 1 April 2015
