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Concept: Nicotinic acetylcholine receptor


Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABAB receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABAB receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain.

Concepts: Nicotine, Pain, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Dextromethorphan


Nicotine cigarette smoke is a large public health burden worldwide, contributing to various types of disease. Anti-tobacco media campaigns and control programs have significantly reduced smoking in the United States, yet trends for menthol cigarette smoking have not been as promising. Menthol cigarette smoking is particularly prevalent among young adults and African Americans, with implications for long-term impacts on health care. Continuing high rates of menthol cigarette addiction call into question the role of menthol in nicotine addiction. To date, a biological basis for the high rate of addiction and relapse among menthol cigarette smokers has not been defined. Studies have demonstrated a role for menthol in the metabolism of nicotine in the body. More recent findings now reveal an interaction between menthol and the nicotinic acetylcholine (nACh) receptor in cells. This receptor is central to the actions of nicotine in the brain, and plays an important role in nicotine addiction. The newly discovered effect of menthol on nACh receptors may begin to explain the unique addictive properties of menthol cigarettes.

Concepts: Smoking, Tobacco smoking, Cigarette, Nicotine, Addiction, Acetylcholine, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor


Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased sugar consumption has been shown to repeatedly elevate dopamine levels in the nucleus accumbens (NAc), in the mesolimbic reward pathway of the brain similar to many drugs of abuse. We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm. Similar results were observed with other nAChR drugs, namely mecamylamine and cytisine. Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward. Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption.

Concepts: Ventral tegmental area, Nicotine, Neurotransmitter, Acetylcholine, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Dopamine, Mesolimbic pathway


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.

Concepts: Nicotine, Acetylcholine, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Ibogaine, Cytisine, Areca nut


The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

Concepts: Nervous system, Receptor, Neurotransmitter, Acetylcholine, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Atropine


Although the activity of the nicotinic acetylcholine receptor (nAChR) is exquisitely sensitive to its membrane environment, the underlying mechanisms remain poorly defined. The homologous prokaryotic pentameric ligand gated ion channel, GLIC, represents an excellent model for probing the molecular basis of nAChR sensitivity due to its high structural homology, ease of expression, and amenability to crystallographic analysis. We show here that membrane-reconstituted GLIC exhibits structural and biophysical properties similar to those of membrane-reconstituted nAChR, although GLIC is substantially more thermally stable. GLIC, however, does not possess the same exquisite lipid sensitivity. In particular, GLIC does not exhibit the same propensity to adopt an uncoupled conformation where agonist binding is uncoupled from channel gating. Structural comparisons provide insight into the chemical features that may predispose the nAChR to the formation of an uncoupled state.

Concepts: Receptor, Acetylcholine, Ion channels, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Ligand-gated ion channel


Smoking is a common addiction and a leading cause of disease. Chronic nicotine exposure is known to activate nicotinic acetylcholine receptors (nAChRs) in immune cells. We demonstrate a novel role for α4 nAChRs in the effect of nicotine on T-cell proliferation and immunity. Using cell based sorting and proteomic analysis we define an α4 nAChR expressing helper T-cell population (α4+CD3+CD4+) and show that this group of cells is responsive to sustained nicotine exposure. In circulation, spleen, and thymus we find that nicotine promotes an increase in CD3+CD4+ cells via its activation of the α4 nAChR and regulation of Gαo, Gprin1, and CDC42 signaling within T-cells. In particular, nicotine is found to promote a Th2, adaptive, immunological response within T-cells, which was absent in α4-/- mice. We thus present a new mechanism of α4 nAChR signaling and immune regulation in T-cells, possibly accounting for the effect of smoking on the immune system.

Concepts: Immune system, White blood cell, Immunology, T helper cell, Nicotine, Cell signaling, Acetylcholine, Nicotinic acetylcholine receptor


Neurotransmitter corelease is emerging as a common theme of central neuromodulatory systems. Though corelease of glutamate or GABA with acetylcholine has been reported within the cholinergic system, the full extent is unknown. To explore synaptic signaling of cholinergic forebrain neurons, we activated choline acetyltransferase expressing neurons using channelrhodopsin while recording post-synaptic currents (PSCs) in layer 1 interneurons. Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors. Based on PSC latency and pharmacological sensitivity, our results suggest monosynaptic release of both GABA and ACh. Anatomical analysis showed that forebrain cholinergic neurons express the GABA synthetic enzyme Gad2 and the vesicular GABA transporter (Slc32a1). We confirmed the direct release of GABA by knocking out Slc32a1 from cholinergic neurons. Our results identify GABA as an overlooked fast neurotransmitter utilized throughout the forebrain cholinergic system. GABA/ACh corelease may have major implications for modulation of cortical function by cholinergic neurons.

Concepts: Nicotine, Neurotransmitter, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, GABAA receptor, Ligand-gated ion channel


Alterations in expression patterns of alpha4beta2 nicotinic acetylcholine receptors (nAChR) have been demonstrated to alter cholinergic neurotransmission and implicated in neurological disorders including Autism, nicotine addiction, Alzheimer’s and Parkinson’s disease. Positive allosteric modulators (PAMs) represent promising new leads in the development of therapeutic agents for the treatment of these disorders. This study investigates the involvement of the beta2 containing subunit interfaces of alpha4beta2 receptors in the modulation of acetylcholine- (ACh) induced responses by the PAM desformylflustrabromine (dFBr). Eight amino acids on the principal face of the beta2 subunit were mutated to alanine in order to explore the involvement of this region in potentiation of ACh-induced currents by dFBr. ACh-induced responses obtained from wild type and mutant alpha4beta2 receptors expressed in Xenopus laevis oocytes were recorded in the presence and absence of dFBr using two-electrode voltage clamp electrophysiology. Wild type and mutant receptors were expressed in both high- (HS) and low- (LS) ACh sensitivity isoforms by using biased injection ratios of 1:5 or 5:1 alpha4: beta2 cRNA. Mutations were made in the B, C and A loops of the principal face of the beta2 subunit; regions not involved in binding of ACh. Mutant β2(Y120A) significantly eliminated dFBr potency in both isoform preparations. Several other mutations altered dFBr potentiation levels in both preparations. Our findings support the involvement of the principal face of the beta2 subunit in dFBr modulation of ACh-induced responses. Findings from this study will aid in the improved design of dFBr-like PAMs for potential therapeutic use.

Concepts: Nicotine, Neurotransmitter, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Alpha-4 beta-2 nicotinic receptor


The multifaceted nature of the pathology of dementia spectrum disorders has complicated their management and the development of effective treatments. This is despite the fact that they are far from uncommon, with Alzheimer’s disease (AD) alone affecting 35 million people worldwide. The cholinergic system has been found to be crucially involved in cognitive function, with cholinergic dysfunction playing a pivotal role in the pathophysiology of dementia. The use of molecular imaging such as SPECT and PET for tagging targets within the cholinergic system has shown promise for elucidating key aspects of underlying pathology in dementia spectrum disorders, including AD or parkinsonian dementias. SPECT and PET studies using selective radioligands for cholinergic markers, such as [(11)C]MP4A and [(11)C]PMP PET for acetylcholinesterase (AChE), [(123)I]5IA SPECT for the α4β2 nicotinic acetylcholine receptor and [(123)I]IBVM SPECT for the vesicular acetylcholine transporter, have been developed in an attempt to clarify those aspects of the diseases that remain unclear. This has led to a variety of findings, such as cortical AChE being significantly reduced in Parkinson’s disease (PD), PD with dementia (PDD) and AD, as well as correlating with certain aspects of cognitive function such as attention and working memory. Thalamic AChE is significantly reduced in progressive supranuclear palsy (PSP) and multiple system atrophy, whilst it is not affected in PD. Some of these findings have brought about suggestions for the improvement of clinical practice, such as the use of a thalamic/cortical AChE ratio to differentiate between PD and PSP, two diseases that could overlap in terms of initial clinical presentation. Here, we review the findings from molecular imaging studies that have investigated the role of the cholinergic system in dementia spectrum disorders.

Concepts: Alzheimer's disease, Parkinson's disease, Parkinsonism, Dementia, Acetylcholine, Nicotinic acetylcholine receptor, Progressive supranuclear palsy, Neuromuscular junction