Using Natural Genetic Variability in Nicotinic Receptor Genes to Understand the Function of Nicotinic Receptors

2016 ◽  
pp. 97-117
Author(s):  
Jennifer A. Wilking ◽  
Jerry A. Stitzel
Keyword(s):  
Genetic Variability ◽  
Nicotinic Receptor ◽  
Nicotinic Receptors

Localisation of two classes of acetylcholine receptor-like molecules in sperms of different animal species

Zygote ◽  
1995 ◽  
Vol 3 (3) ◽  
pp. 207-217 ◽  
Author(s):  
B. Baccetti ◽  
A.G. Burrini ◽  
G. Collodel ◽  
C. Falugi ◽  
E. Moretti ◽  
...  
Keyword(s):  
Nicotinic Receptor ◽  
Nicotinic Receptors ◽  
Animal Species ◽  
Distribution Patterns ◽  
Sperm Head ◽  
Similar Distribution ◽  
Vertebrate Species ◽  
Immunogold Staining ◽  
Specific Antibodies ◽  
Transduction Mechanisms

SummaryThe distribution of different classes of acetylcholine (ACh) receptor-like molecules in sperms of different invertebrate and vertebrate species is described. ACh receptor molecules belong to one of two classes: muscarinic receptors (mAChRs), associated with signal transduction mechanisms in the inner domain of the cell, and nicotinic receptors (nAChRs), capable of opening Na+ channels when activated by the ligand. Molecules immunologically related to mAChRs and to ACh can be identified by specific antibodies, and revealed by immunofluorescent or immunogold staining; the nicotinic receptor-like molecules are localised as curare-sensitive affinity sites for α-bungarotoxin. In all species studied, both classes of receptors were found, with a similar distribution. Muscarinic-like molecules were found mainly in the sperm head regions of most species; such a localisation may be correlated to a function in sperm–egg interaction, for instance in the regulation of the block to polyspermy. Nicotinic-like molecules are present mainly in the tail and in the post-acrosomal region of most animals, thus confirming their function in the regulation of sperm propulsion, but are also present at the acrosomal region of most species. The distribution patterns of the different classes of molecules indicate that both may be in sperm–egg interactions, in addition to their known function in the regulation of sperm propulsion.

NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action

2005 ◽  
Vol 45 (1) ◽  
pp. 247-268 ◽  
Author(s):  
Motohiro Tomizawa ◽  
John E. Casida
Keyword(s):  
Nicotinic Receptor ◽  
Nicotinic Receptors ◽  
Crop Protection ◽  
Selective Action ◽  
Flea Control ◽  
Major Class ◽  
Toxicological Profile ◽  
Neonicotinoid Insecticide ◽  
Low Toxicity ◽  
Detoxification Mechanisms

The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-π interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate relative to insect nicotinic receptors is a major factor in their favorable toxicological profile.

scholarly journals Nicotinic acetylcholine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Cecilia Gotti ◽  
Michael. J. Marks ◽  
Neil S. Millar ◽  
Susan Wonnacott
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Nicotinic Receptor ◽  
Acetylcholine Receptors ◽  
Nicotinic Receptors ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Nicotinic Acetylcholine ◽  
Α Subunit

Nicotinic acetylcholine receptors are members of the Cys-loop family of transmitter-gated ion channels that includes the GABAA, strychnine-sensitive glycine and 5-HT3 receptors [210, 3, 155, 220, 252]. All nicotinic receptors are pentamers in which each of the five subunits contains four α-helical transmembrane domains. Genes encoding a total of 17 subunits (α1-10, β1-4, γ, δ and ε) have been identified [117]. All subunits with the exception of α8 (present in avian species) have been identified in mammals. All α subunits possess two tandem cysteine residues near to the site involved in acetylcholine binding, and subunits not named α lack these residues [155]. The orthosteric ligand binding site is formed by residues within at least three peptide domains on the α subunit (principal component), and three on the adjacent subunit (complementary component). nAChRs contain several allosteric modulatory sites. One such site, for positive allosteric modulators (PAMs) and allosteric agonists, has been proposed to reside within an intrasubunit cavity between the four transmembrane domains [257, 85]; see also [103]). The high resolution crystal structure of the molluscan acetylcholine binding protein, a structural homologue of the extracellular binding domain of a nicotinic receptor pentamer, in complex with several nicotinic receptor ligands (e.g.[33]) and the crystal structure of the extracellular domain of the α1 subunit bound to α-bungarotoxin at 1.94 Å resolution [53], has revealed the orthosteric binding site in detail (reviewed in [210, 117, 37, 193]). Nicotinic receptors at the somatic neuromuscular junction of adult animals have the stoichiometry (α1)2β1δε, whereas an extrajunctional (α1)2β1γδ receptor predominates in embryonic and denervated skeletal muscle and other pathological states. Other nicotinic receptors are assembled as combinations of α(2-6) and &beta(2-4) subunits. For α2, α3, α4 and β2 and β4 subunits, pairwise combinations of α and β (e.g. α3β4 and α4β2) are sufficient to form a functional receptor in vitro, but far more complex isoforms may exist in vivo (reviewed in [94, 91, 155]). There is strong evidence that the pairwise assembly of some α and β subunits can occur with variable stoichiometry [e.g. (α4)2(β2)2 or (α4)3(β2)2] which influences the biophysical and pharmacological properties of the receptor [155]. α5 and β3 subunits lack function when expressed alone, or pairwise, but participate in the formation of functional hetero-oligomeric receptors when expressed as a third subunit with another α and β pair [e.g. α4α5αβ2, α4αβ2β3, α5α6β2, see [155] for further examples]. The α6 subunit can form a functional receptor when co-expressed with β4 in vitro, but more efficient expression ensues from incorporation of a third partner, such as β3 [256]. The α7, α8, and α9 subunits form functional homo-oligomers, but can also combine with a second subunit to constitute a hetero-oligomeric assembly (e.g. α7β2 and α9α10). For functional expression of the α10 subunit, co-assembly with α9 is necessary. The latter, along with the α10 subunit, appears to be largely confined to cochlear and vestibular hair cells. Comprehensive listings of nicotinic receptor subunit combinations identified from recombinant expression systems, or in vivo, are given in [155]. In addition, numerous proteins interact with nicotinic ACh receptors modifying their assembly, trafficking to and from the cell surface, and activation by ACh (reviewed by [154, 9, 115]).The nicotinic receptor Subcommittee of NC-IUPHAR has recommended a nomenclature and classification scheme for nicotinic acetylcholine (nACh) receptors based on the subunit composition of known, naturally- and/or heterologously-expressed nACh receptor subtypes [139]. Headings for this table reflect abbreviations designating nACh receptor subtypes based on the predominant α subunit contained in that receptor subtype. An asterisk following the indicated α subunit denotes that other subunits are known to, or may, assemble with the indicated α subunit to form the designated nACh receptor subtype(s). Where subunit stoichiometries within a specific nACh receptor subtype are known, numbers of a particular subunit larger than 1 are indicated by a subscript following the subunit (enclosed in parentheses – see also [44]).

The effect of coniine on presynaptic nicotinic receptors

2016 ◽  
Vol 71 (5-6) ◽  
pp. 115-120 ◽  
Author(s):  
Ulkem Erkent ◽  
Alper B. Iskit ◽  
Rustu Onur ◽  
Mustafa Ilhan
Keyword(s):  
Guinea Pig ◽  
Nicotinic Receptor ◽  
Nicotinic Receptors ◽  
Clinical Signs ◽  
Toxicological Effects ◽  
Conium Maculatum ◽  
Anococcygeus Muscle ◽  
Rat Anococcygeus Muscle

Abstract Toxicity of coniine, an alkaloid of Conium maculatum (poison hemlock), is manifested by characteristic nicotinic clinical signs including excitement, depression, hypermetria, seizures, opisthotonos via postsynaptic nicotinic receptors. There is limited knowledge about the role of presynaptic nicotinic receptors on the pharmacological and toxicological effects of coniine in the literature. The present study was undertaken to evaluate the possible role of presynaptic nicotinic receptors on the pharmacological and toxicological effects of coniine. For this purpose, the rat anococcygeus muscle and guinea-pig atria were used in vitro. Nicotine (100 μM) elicited a biphasic response composed of a relaxation followed by contraction through the activation of nitrergic and noradrenergic nerve terminals in the phenylephrine-contracted rat anococcygeus muscle. Coniine inhibited both the nitrergic and noradrenergic response in the muscle (–logIC50 = 3.79 ± 0.11 and –logIC50 = 4.57 ± 0.12 M, respectively). The effect of coniine on nicotinic receptor-mediated noradrenergic transmission was also evaluated in the guinea-pig atrium (–logIC50 = 4.47 ± 0.12 M) and did not differ from the –logIC50 value obtained in the rat anococcygeus muscle. This study demonstrated that coniine exerts inhibitory effects on nicotinic receptor-mediated nitrergic and noradrenergic transmitter response.

Acetylcholine may regulate its own nicotinic receptor-channel through the C-kinase system

1987 ◽  
Vol 230 (1260) ◽  
pp. 355-365 ◽  
Keyword(s):  
Chick Embryo ◽  
Cell Membrane ◽  
Patch Clamp ◽  
Nicotinic Receptor ◽  
Nicotinic Receptors ◽  
Pkc Inhibitor ◽  
Open Time ◽  
Patch Pipette ◽  
Channel Properties ◽  
Receptor Channel

Acetylcholine (ACh)-activated channel properties were examined on an aneural culture of chick embryo myotubes by using patch-clamp techniques. Changes in conductance, open time and closed time were induced by the selective activator of the calcium- and phospholipid-dependent C-kinase (PKc), 12- O -tetradecanoylphorbol-13-acetate (TPA). The action of TPA was mimicked by exogenous phospholipase C and was blocked by the PKc inhibitor, 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine. In addition to its gating action, ACh was shown to stimulate phosphoinositide turnover and to translocate PKc from the cytosol to the cell membrane. Both these ACh-induced effects were inhibited by curare and not substantially affected by atropine. Bath-applied ACh outside the patch-pipette in the cell-attached patch-clamp mode, had a strong effect on the ACh-activated channels in the patch membrane, in a way that resembled the action of TPA . These findings raise the possibility that ACh regulates its own nicotinic receptors through the C-kinase system.

Desensitisation of chromaffin cell nicotinic receptors does not impede catecholamine secretion during acute hypoxia in rainbow trout (Oncorhynchus mykiss)

2000 ◽  
Vol 203 (10) ◽  
pp. 1589-1597 ◽  
Author(s):  
K.N. Lapner ◽  
C.J. Montpetit ◽  
S.F. Perry
Keyword(s):  
Nicotinic Receptor ◽  
Nicotinic Receptors ◽  
Acute Hypoxia ◽  
Plasma Catecholamine ◽  
Cardinal Vein ◽  
Plasma Adrenaline ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Posterior Cardinal Vein ◽  
Receptor Desensitisation

Experiments were performed on adult rainbow trout (Oncorhynchus mykiss) in vivo using chronically cannulated fish and in situ using a perfused posterior cardinal vein preparation (i) to characterise the desensitisation of chromaffin cell nicotinic receptors and (ii) to assess the ability of fish to secrete catecholamines during acute hypoxia with or without functional nicotinic receptors. Intra-arterial injection of nicotine (6.0×10(−)(7)mol kg(−)(1)) caused a rapid increase in plasma adrenaline and noradrenaline levels; the magnitude of this response was unaffected by an injection of nicotine given 60 min earlier. Evidence for nicotinic receptor desensitisation, however, was provided during continuous intravenous infusion of nicotine (1.3×10(−)(5)mol kg(−)(1)h(−)(1)) in which plasma catecholamine levels increased initially but then returned to baseline levels. To ensure that the decline in circulating catecholamine concentrations during continuous nicotine infusion was not related to changes in storage levels or altered rates of degradation/clearance, in situ posterior cardinal vein preparations were derived from fish previously experiencing 60 min of saline or nicotine infusion. Confirmation of nicotinic receptor desensitisation was provided by demonstrating that the preparations derived from nicotine-infused fish were unresponsive to nicotine (10(−)(5)mol l(−)(1)), yet remained responsive to angiotensin II (500 pmol kg(−)(1)). The in situ experiments demonstrated that desensitisation of the nicotinic receptor occurred within 5 min of receptor stimulation and that resensitisation was established 40 min later. The ability to elevate plasma catecholamine levels during acute hypoxia (40–45 mmHg; 5.3-6.0 kPa) was not impaired in fish experiencing nicotinic receptor desensitisation. Indeed, peak plasma adrenaline levels were significantly higher in the desensitised fish during hypoxia than in controls (263+/−86 versus 69+/−26 nmol l(−)(1); means +/− s.e.m., N=6-9). Thus, the results of the present study demonstrate that activation of preganglionic sympathetic cholinergic nerve fibres and the resultant stimulation of nicotinic receptors is not the sole mechanism for eliciting catecholamine secretion during hypoxia.

scholarly journals Full activation of an α7-α3β4 nicotinic receptor complex avoids receptor desensitization in human chromaffin cells

2020 ◽  
Author(s):  
Amanda Jiménez-Pompa ◽  
Sara Sanz-Lázaro ◽  
José Medina-Polo ◽  
Carmen González-Enguita ◽  
Jesús Blázquez ◽  
...  
Keyword(s):  
Nicotinic Receptor ◽  
Chromaffin Cells ◽  
Nicotinic Receptors ◽  
Adrenal Glands ◽  
Gradual Increase ◽  
Receptor Complex ◽  
Receptor Desensitization ◽  
Partial Activation ◽  
Full Activation

Abstractα7 nicotinic receptors have been involved in numerous pathologies. A hallmark of these receptors is their extremely fast desensitization, a process not fully understood yet. Here we show that human native α7 and α3β4 nicotinic receptors physically interact in human chromaffin cells of adrenal glands. The full activation of this α7-α3β4 receptor complex avoids subtypes receptor desensitization, leading to gradual increase of currents with successive acetylcholine pulses. Instead, full and partial activation with choline of α7 and α3β4 subtypes, respectively, of this linked receptor leads to α7 receptor desensitization. Therefore choline, a product of the acetylcholine hydrolysis, acts as a brake by limiting the increase of currents by acetylcholine. Very importantly, the efficiency of the α7-α3β4 interaction diminishes in subjets older than 50 years, accordingly increasing receptor desensitization and decreasing nicotinic currents. These results open a new line of research to achieve improved therapeutic treatments for nicotinic receptors related diseases.

scholarly journals Molecular Mimicry Between the Rabies Virus Glycoprotein and Human Immunodeficiency Virus-1 GP120: Cross-Reacting Antibodies Induced by Rabies Vaccination

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3623-3628 ◽  
Author(s):  
Luisa Bracci ◽  
Samir K. Ballas ◽  
Adriano Spreafico ◽  
Paolo Neri
Keyword(s):  
Human Immunodeficiency Virus ◽  
Rabies Virus ◽  
Receptor Binding ◽  
Nicotinic Receptor ◽  
Nicotinic Receptors ◽  
Molecular Mimicry ◽  
Rabies Virus Glycoprotein ◽  
Virus Glycoprotein ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract The 160-170 sequence of human immunodeficiency virus (HIV)-1 gp120 mimics a nicotinic receptor-binding motif of rabies virus glycoprotein and snake neurotoxins. This sequence has been proposed to be involved in the binding of HIV-1 gp120 to the acetylcholine binding sites of nicotinic receptors. By using biomolecular interaction analysis (BIA) technology we have found that HIV-1 gp120 can bind to detergent-extracted nicotinic receptor from fetal calf muscle. The binding is inhibited by nicotine and by a synthetic peptide reproducing the gp120 160-170 sequence. The molecular mimicry between gp120 and rabies virus glycoprotein is confirmed by cross-reacting antibodies. We have found that vaccination against rabies can induce the production of anti–HIV-1 gp120 antibodies in humans. The cross-reacting antibodies are directed to the gp120 sequence involved in the mimicry with the rabies virus glycoprotein. The cross-reactivity between the rabies virus and HIV-1 has important implications in transfusion medicine. Moreover, the presence of cross-reacting antibodies between the nicotinic receptor binding site of rabies virus glycoprotein and a fragment of HIV-1 gp120 strengthens the hypothesis about the possible role of nicotinic receptors as potential receptors for HIV-1 in the central nervous system.

Receptor subtypes mediating depressor responses to microinjections of nicotine into medial NTS of the rat

2000 ◽  
Vol 279 (1) ◽  
pp. R132-R140 ◽  
Author(s):  
S. Dhar ◽  
F. Nagy ◽  
J. M. McIntosh ◽  
H. N. Sapru
Keyword(s):  
Nicotinic Receptor ◽  
Nicotinic Receptors ◽  
Wistar Rats ◽  
Excitatory Amino Acid ◽  
Receptor Subtypes ◽  
Solitary Tract ◽  
Excitatory Amino Acid Receptors ◽  
Amino Acid Receptors ◽  
Predominant Type ◽  
Male Wistar Rats

Microinjections (50 nl) of nicotine (0.01–10 μM) into the nucleus of the solitary tract (NTS) of adult, urethan-anesthetized, artificially ventilated, male Wistar rats, elicited decreases in blood pressure and heart rate. Prior microinjections of α-bungarotoxin (α-BT) and α-conotoxin ImI (specific toxins for nicotinic receptors containing α7 subunits) elicited a 20–38% reduction in nicotine responses. Similarly, prior microinjections of hexamethonium, mecamylamine, and α-conotoxin AuIB (specific blockers or toxin for nicotinic receptors containing α3β4 subunits) elicited a 47–79% reduction in nicotine responses. Nicotine responses were completely blocked by prior sequential microinjections of α-BT and mecamylamine into the NTS. Complete blockade of excitatory amino acid receptors (EAARs) in the NTS did not attenuate the responses to nicotine. It was concluded that 1) the predominant type of nicotinic receptor in the NTS contains α3β4 subunits, 2) a smaller proportion contains α7 subunits, 3) the presynaptic nicotinic receptors in the NTS do not contribute to nicotine-induced responses, and 4) EAARs in the NTS are not involved in mediating responses to nicotine.

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