This review covers history underlying the discovery of the molecular mediators of nicotine's effects in the brain and the diversity of the nicotinic acetylcholine receptor (nAChR) subtypes. Models ...are presented for both their structure and their function as mediators of signal transduction, with special consideration of the differences between the two main subtypes: heteromeric receptors, which are specialized for rapid electrochemical signal transduction, and homomeric α7 receptors, which have come to be implicated in both ionotropic and metabotropic signaling. This review presents perspectives on the pharmacology and therapeutic targeting of nAChRs for the treatment of nicotine dependence or disease.
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Although α2 was the first neuronal nicotinic acetylcholine receptor (nAChR) receptor subunit to be cloned, due to its low level of expression in rodent brain, its study has largely ...been neglected. This study provides a comparison of the α2 and α4 structures and their functional similarities, especially in regard to the existence of low and high sensitivity forms based on subunit stoichiometry. We show that the pharmacological profiles of the low and high sensitivity forms of α2β2 and α4β2 receptors are very similar in their responses to nicotine, with high sensitivity receptors showing protracted responses. Sazetidine A, an agonist that is selective for the high sensitivity α4 receptors also selectively activates high sensitivity α2 receptors. Likewise, α2 receptors have similar responses as α4 receptors to the positive allosteric modulators (PAMs) desformylflustrabromine (dFBr) and NS9283. We show that the partial agonists for α4β2 receptors, cytisine and varenicline are also partial agonists for α2β2 receptors. Studies have shown that levels of α2 expression may be much higher in the brains of primates than those of rodents, suggesting a potential importance for human therapeutics. High-affinity nAChR have been studied in humans with PET ligands such as flubatine. We show that flubatine has similar activity with α2β2 and α4β2 receptors so that α2 receptors will also be detected in PET studies that have previously presumed to selectively detect α4β2 receptors. Therefore, α2 receptors need more consideration in the development of therapeutics to manage nicotine addiction and declining cholinergic function in age and disease.
Postsynaptic nAChRs in the peripheral nervous system are critical for neuromuscular and autonomic neurotransmission. Pre- and peri-synaptic nAChRs in the brain modulate neurotransmission and are ...responsible for the addictive effects of nicotine. Subtypes of nAChRs in lymphocytes and non-synaptic locations may modulate inflammation and other cellular functions. All AChRs that function as ligand-gated ion channels are formed from five homologous subunits organized to form a central cation channel whose opening is regulated by ACh bound at extracellular subunit interfaces. nAChR subtype subunit composition can range from α7 homomers to α4β2α6β2β3 heteromers. Subtypes differ in affinities for ACh and other agonists like nicotine and in efficiencies with which their channels are opened and desensitized. Subtypes also differ in affinities for antagonists and for positive and negative allosteric modulators. Some agonists are “silent” with respect to channel opening, and AChRs may be able to signal metabotropic pathways by releasing G-proteins independent of channel opening. Electrophysiological studies that can resolve single-channel openings and molecular genetic approaches have allowed characterization of the structures of ligand binding sites, the cation channel, and the linkages between them, as well as the organization of AChR subunits and their contributions to function. Crystallography and cryo-electron-microscopy are providing increasing insights into the structures and functions of AChRs. However, much remains to be learned about both AChR structure and function, the in vivo functional roles of some AChR subtypes, and the development of better pharmacological tools directed at AChRs to treat addiction, pain, inflammation, and other medically important issues.
This article is part of the special issue on ‘Contemporary Advances in Nicotine Neuropharmacology’.
•Nicotinic acetylcholine receptors (nAChR) function as ligand-gated ion channels.•nAChR play diverse and important roles in the central nervous system.•Neuronal nAChR are important therapeutic targets, responsive to ACh and other drugs.•Neuronal nAChR may function as metabotropic receptors in non-neuronal cells.•Newly discovered allosteric ligands and modulators expand therapeutic possibilities.
Habitual chewing of "betel nut" preparations constitutes the fourth most common human self-administration of a psychoactive substance after alcohol, caffeine, and nicotine. The primary active ...ingredient in these preparations is arecoline, which comes from the areca nut, the key component of all such preparations. Arecoline is known to be a relatively non-selective muscarinic partial agonist, accounting for many of the overt peripheral and central nervous system effects, but not likely to account for the addictive properties of the drug. We report that arecoline has activity on select nicotinic acetylcholine receptor (nAChR) subtypes, including the two classes of nAChR most related to the addictive properties of nicotine: receptors containing α4 and β2 subunits and those which also contain α6 and β3 subunits. Arecoline is a partial agonist with about 6-10% efficacy for the α4* and α6* receptors expressed in Xenopus oocytes. Additionally, arecoline is a silent agonist of α7 nAChR; while it does not activate α7 receptors when applied alone, it produces substantial activation when co-applied with the positive allosteric modulator PNU-120696. Some α7 silent agonists are effective inhibitors of inflammation, which might account for anti-inflammatory effects of arecoline. Arecoline's activity on nAChR associated with addiction may account for the habitual use of areca nut preparations in spite of the well-documented risk to personal health associated with oral diseases and cancer. The common link between betel and tobacco suggests that partial agonist therapies with cytisine or the related compound varenicline may also be used to aid betel cessation attempts.
This review discusses the diverse effects of nicotine on the various nicotinic acetylcholine receptors of the central and peripheral nervous system and how those effects may promote the usage and ...addiction to tobacco products.
Highlights • Intracellular domains of Cys -loop receptors are variable and unique to each subunit. • Intracellular subdomains may contribute to ion-conducting submembrane portals. • The α7 ...intracellular domains contain well-conserved sites for protein interactions.
The
7-type nicotinic acetylcholine receptor is one of the most unique and interesting of all the members of the cys-loop superfamily of ligand-gated ion channels. Since it was first identified ...initially as a binding site for
-bungarotoxin in mammalian brain and later as a functional homomeric receptor with relatively high calcium permeability, it has been pursued as a potential therapeutic target for numerous indications, from Alzheimer disease to asthma. In this review, we discuss the history and state of the art for targeting
7 receptors, beginning with subtype-selective agonists and the basic pharmacophore for the selective activation of
7 receptors. A key feature of
7 receptors is their rapid desensitization by standard "orthosteric" agonist, and we discuss insights into the conformational landscape of
7 receptors that has been gained by the development of ligands binding to allosteric sites. Some of these sites are targeted by positive allosteric modulators that have a wide range of effects on the activation profile of the receptors. Other sites are targeted by direct allosteric agonist or antagonists. We include a perspective on the potential importance of
7 receptors for metabotropic as well as ionotropic signaling. We outline the challenges that exist for future development of drugs to target this important receptor and approaches that may be considered to address those challenges. SIGNIFICANCE STATEMENT: The
7-type nicotinic acetylcholine receptor (nAChR) is acknowledged as a potentially important therapeutic target with functional properties associated with both ionotropic and metabotropic signaling. The functional properties of
7 nAChR can be regulated in diverse ways with the variety of orthosteric and allosteric ligands described in this review.
Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions ...between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high-affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues.