more information
Search within Results:

Select All    Deselect All
 |   | 
Details
   print
  Records Links
Author (up) Arias, H.R. file  url
openurl 
  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  
Permanent link to this record
 

 
Author (up) Briggs, C.A.; Gronlien, J.H.; Curzon, P.; Timmermann, D.B.; Ween, H.; Thorin-Hagene, K.; Kerr, P.; Anderson, D.J.; Malysz, J.; Dyhring, T.; Olsen, G.M.; Peters, D.; Bunnelle, W.H.; Gopalakrishnan, M. file  url
openurl 
  Title Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors Type Journal Article
  Year 2009 Publication British Journal of Pharmacology Abbreviated Journal Br J Pharmacol  
  Volume 158 Issue 6 Pages 1486-1494  
  Keywords Allosteric Regulation; Animals; Avoidance Learning/drug effects; Azabicyclo Compounds/administration & dosage/*pharmacology; Behavior, Animal/drug effects; Cell Line; Cognition Disorders/drug therapy/physiopathology; Dose-Response Relationship, Drug; Furans/administration & dosage/*pharmacology; Humans; Male; Mice; Nicotinic Agonists/*pharmacology; Oocytes/drug effects/metabolism; Oxadiazoles/administration & dosage/*pharmacology; Pyridazines/pharmacology; Pyrroles/pharmacology; Rats; Receptors, Nicotinic/*drug effects/metabolism; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract BACKGROUND AND PURPOSE: Several agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved. EXPERIMENTAL APPROACH: Two structurally related alpha7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. KEY RESULTS: NS6784 activated human and rat alpha7 nAChR with EC(50)s of 0.72 and 0.88 microM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha7 nAChR (<2% in oocytes, < or =8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha7 nAChRs or using the slowly desensitizing alpha7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941. CONCLUSIONS AND IMPLICATIONS: Collectively, these findings suggest that a degree of alpha7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha7 nAChR antagonists with favourable CNS penetration.  
  Call Number Serial 1881  
Permanent link to this record
 

 
Author (up) Clark, A.; Lindgren, S.; Brooks, S.P.; Watson, W.P.; Little, H.J. file  url
openurl 
  Title Chronic infusion of nicotine can increase operant self-administration of alcohol Type Journal Article
  Year 2001 Publication Neuropharmacology Abbreviated Journal Neuropharmacology  
  Volume 41 Issue 1 Pages 108-117  
  Keywords Alcohol Drinking/*psychology; Animals; Central Nervous System Depressants/administration & dosage/*pharmacology; Conditioning, Operant/drug effects; Ethanol/administration & dosage/*pharmacology; Infusion Pumps, Implantable; Male; Nicotine/*pharmacology; Nicotinic Agonists/*pharmacology; Rats; Reinforcement Schedule  
  Abstract Effects of nicotine, administered by continuous infusion via osmotic minipumps, were studied on the operant self-administration of alcohol by rats, using a variable interval (15 s) schedule, and measuring the acquisition, maintenance, extinction and reinstatement of responding for alcohol. Doses of nicotine of 0.25, 1.25 and 7.5 mg/kg/24 h had no significant effects on the maintenance of responding for alcohol, but 5 mg/kg/24 h nicotine resulted in a significant increase in responding on the lever delivering the reward when water was substituted for the alcohol, indicating delayed extinction of responding. During infusion of 2.5 mg/kg/24 h nicotine, responding was significantly greater over the “sucrose-fading” training sessions, during acquisition of responding, when mixtures of alcohol and sucrose were provided as reward. When minipumps infusing 2.5 mg/kg/24 h nicotine were implanted after the alcohol responding had been acquired, the responding for alcohol increase during the first week of nicotine infusion, but corresponding nicotine infusion doses of 0.25, 1.25 and 7.5 had no significant effects. The results indicate that nicotine can increase operant responding for alcohol and this is crucially dependent on the dose of nicotine and the time of testing. The results have implications for the frequently encountered dependence on the combination of alcohol and nicotine.  
  Call Number Serial 1172  
Permanent link to this record
 

 
Author (up) Lagostena, L.; Danober, L.; Challal, S.; Lestage, P.; Mocaer, E.; Trocme-Thibierge, C.; Cherubini, E. file  url
doi  openurl
  Title Modulatory effects of S 38232, a non alpha-7 containing nicotine acetylcholine receptor agonist on network activity in the mouse hippocampus Type Journal Article
  Year 2010 Publication Neuropharmacology Abbreviated Journal Neuropharmacology  
  Volume 58 Issue 4-5 Pages 806-815  
  Keywords Animals; Cholinergic Agonists/pharmacology; Dose-Response Relationship, Drug; Excitatory Postsynaptic Potentials/drug effects/physiology; Female; Hippocampus/*drug effects/physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Net/*drug effects/physiology; Nicotinic Agonists/*pharmacology; Rats; *Receptors, Nicotinic/physiology; Torpedo; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract Extracellular field potentials (fEPSPs) and whole cell patch-clamp recordings were used to test the effect of S 38232, a newly developed potent non-alpha7 nicotinic acetylcholine receptors (nAChR) agonist, on synaptic transmission in hippocampal slices obtained from adult mice. S 38232 increased the amplitude of fEPSPs, evoked in stratum radiatum by Schaffer collateral stimulation. This effect was potentiated by picrotoxin, suggesting that S 38232 exerts at least in part its effect on GABAergic interneurons. The action of S 38232 was mediated by non-alpha7 containing nAChRs since it was prevented by DHbetaE (1muM) but not by alpha-BTX (100nM). A similar potentiating effect on fEPSPs was observed when nicotine (1muM) was applied to hippocampal slices obtained from alpha7 -/- mice in the presence of picrotoxin. The potentiating effect of S 38232 was probably presynaptic in origin since it was associated with a significant reduction in paired-pulse ratio. In addition, in patch clamp experiments, S 38232 enhanced the frequency (but not the amplitude) of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs, sIPSCs) recorded from CA1 principal cells. Moreover, it enhanced the frequency of miniature IPSCs but not EPSCs, suggesting that it was acting on nAChRs located on presynaptic/pre-terminal regions of GABAergic interneurons. The effect of S 38232 on GABAergic signaling was concentration-dependent with an EC(50) of 43muM. In conclusions, we present evidence that the new nicotine ligand S 38232, by selectively activating non-alpha7 nAChRs located on principal cells and GABAergic interneurons, influences network activity and information processing in the hippocampus.  
  Call Number Serial 1082  
Permanent link to this record
 

 
Author (up) Yu, M.; Liu, Q.; Sun, J.; Yi, K.; Wu, L.; Tan, X. file  url
doi  openurl
  Title Nicotine improves the functional activity of late endothelial progenitor cells via nicotinic acetylcholine receptors Type Journal Article
  Year 2011 Publication Biochemistry and Cell Biology = Biochimie et Biologie Cellulaire Abbreviated Journal Biochem Cell Biol  
  Volume 89 Issue 4 Pages 405-410  
  Keywords Bungarotoxins/pharmacology; Cell Adhesion/drug effects; Cell Movement/drug effects; Cell Shape; Cell Survival/drug effects; Cells, Cultured; Endothelial Cells/*drug effects/physiology; Fetal Blood/cytology; Humans; Infant, Newborn; Mecamylamine/pharmacology; Neovascularization, Physiologic/drug effects; Nicotine/*pharmacology; Nicotinic Agonists/*pharmacology; Nicotinic Antagonists/pharmacology; Receptors, Nicotinic; Stem Cells/*drug effects/physiology  
  Abstract The aim of this study is to investigate whether nicotinic acetylcholine receptors (nAChRs) are involved in the modulation of functional activity of late endothelial progenitor cells (EPCs) induced by nicotine. Total mononuclear cells (MNCs) were isolated from human umbilical cord blood by Ficoll density gradient centrifugation, and then the cells were plated on fibronectin-coated culture plates. Late EPCs were positive for 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine-labeled acetylated low-density lipoprotein (DiI-acLDL) uptake and fluorescein-isothiocyanate-conjugated Ulex europaeus agglutinin lectin (UEA-1) binding. Expression of von Willbrand factor (vWF), kinase insert domain receptor (KDR), and alpha7 nAChR was detected by indirect immunofluorescence staining. Late EPCs of 3-5 passages were treated for 32 h with either vehicle or nicotine with or without pre-incubation of nAChR antagonism, mecamylamine, or alpha-bungarotoxin. The viability, migration, and in vitro vasculogenesis activity of late EPCs were assayed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, modified Boyden chamber assay, and in vitro angiogenesis assay, respectively. Late EPCs adhesion assay was performed by replating cells on fibronectin-coated plates, and then adherent cells were counted. Incubation with 10 nmol/L nicotine enhanced viable, migratory, adhesive, and in vitro vasculogenesis capacity of late EPCs. The effect of nicotine on late EPCs can be attenuated by mecamylamine or alpha-bungarotoxin. In conclusion, nicotine improves the functional activity of late EPCs via nAChRs.  
  Call Number Serial 431  
Permanent link to this record
Select All    Deselect All
 |   | 
Details
   print

Save Citations: