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nAChR Subtypes (nachr + subtype)

Distribution by Scientific Domains
Medical Sciences57%
Life Sciences42%

Selected Abstracts

Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons

THE JOURNAL OF PHYSIOLOGY, Issue 2 2009
Kechun Yang
Dopaminergic (DAergic) neuronal activity in the ventral tegmental area (VTA) is thought to contribute generally to pleasure, reward, and drug reinforcement and has been implicated in nicotine dependence. nAChRs expressed in the VTA exhibit diverse subunit compositions, but the functional and pharmacological properties are largely unknown. Here, using patch-clamp recordings in single DAergic neurons freshly dissociated from rat VTA, we clarified three functional subtypes of nAChRs (termed ID, IID and IIID receptors) based on whole-cell current kinetics and pharmacology. Kinetic analysis demonstrated that comparing to ID, IID receptor-mediated current had faster activation and decay constant and IIID receptor-mediated current had larger current density. Pharmacologically, ID receptor-mediated current was sensitive to the ,4,2-nAChR agonist RJR-2403 and antagonist dihydro-,-erythroidine (DH,E); IID receptor-mediated current was sensitive to the selective ,7-nAChR agonist choline and antagonist methyllycaconitine (MLA); while IIID receptor-mediated current was sensitive to the ,4-containing nAChR agonist cytisine and antagonist mecamylamine (MEC). The agonist concentration,response relationships demonstrated that IID receptor-mediated current exhibited the highest EC50 value compared to ID and IIID receptors, suggesting a relatively low agonist affinity of type IID receptors. These results suggest that the type ID, IID and IIID nAChR-mediated currents are predominately mediated by activation of ,4,2-nAChR, ,7-nAChR and a novel nAChR subtype(s), respectively. Collectively, these findings indicate that the VTA DAergic neurons express diversity and multiplicity of functional nAChR subtypes. Interestingly, each DAergic neuron predominantly expresses only one particularly functional nAChR subtype, which may have distinct but important roles in regulation of VTA DA neuronal function, DA transmission and nicotine dependence. [source]

Selectivity of lynx proteins on insect nicotinic acetylcholine receptors in the brown planthopper, Nilaparvata lugens

INSECT MOLECULAR BIOLOGY, Issue 3 2010
B. Yang
Abstract Neuronal nicotinic acetylcholine receptors (nAChRs) are major excitatory neurotransmitter receptors in both vertebrates and invertebrates. Two lynx proteins (Nl-lynx1 and Nl-lynx2) have been identified in the brown planthopper, Nilaparvata lugens, which act as modulators on insect nAChRs. In the present study, two lynx proteins were found to act on the triplet receptor Nl,1/Nl,2/,2 expressed in Xenopus oocytes, increasing agonist-evoked macroscopic currents, but not changing agonist sensitivity and desensitization properties. Nl-lynx1 and Nl-lynx2 increased Imax (maximum responses) of acetylcholine to 4.85-fold and 2.40-fold of that of Nl,1/Nl,2/,2 alone, and they also increased Imax of imidacloprid to 2.57-fold and 1.25-fold. Although, on another triplet nAChRs Nl,3/Nl,8/,2, Nl-lynx2 increased Imax of acetylcholine and imidacloprid to 3.63-fold and 2.16-fold, Nl-lynx1 had no effects on Imax of either acetylcholine or imidacloprid. The results demonstrate the selectivity of lynx proteins for different insect nAChR subtypes. This selectivity was also identified in native N. Lugens. Co-immunoprecipitation was found between Nl,1/Nl,2-containing receptors and both Nl-lynx1 and Nl-lynx2, but was only found between Nl,3/Nl,8-containing receptors and Nl-lynx2. When the previously identified Nl,1Y151S and Nl,3Y151S mutations were included (Nl,1Y151S/Nl,2/,2 and Nl,3Y151S/Nl,8/,2), the increase in Imax of imidacloprid, but not acetylcholine, caused by co-expression of Nl-lynx1 and Nl-lynx2 was more noticeable than that of their wildtype counterparts. Taken together, these data suggest that two modulators, Nl-lynx1 and Nl-lynx2, might serve as an influencing factor in target site insensitivity in N. lugens, such as Y151S mutation. [source]

Deletion of the ,7 Nicotinic Receptor Subunit Gene Results in Increased Sensitivity to Several Behavioral Effects Produced by Alcohol

ALCOHOLISM, Issue 3 2005
Barbara J. Bowers
Background: The finding that most people with alcoholism are also heavy smokers prompted several research groups to evaluate the effects of ethanol on neuronal nicotinic acetylcholine receptor (nAChR) function. Data collected in vitro indicate that physiologically relevant concentrations of ethanol inhibit the functional activation of homomeric ,7 nAChRs, which are one of the most abundant nAChR subtypes expressed in the mammalian brain. The studies outlined here used ,7 gene knockout (null mutant) mice to evaluate the potential role of ,7 nAChRs in modulating selected behavioral and physiological effects produced by ethanol. Methods: Current evidence indicates that many responses to ethanol are not genetically correlated. Therefore, the authors measured the effects of acute administration of ethanol on several behaviors that are altered by both ethanol and nicotine: two tests of locomotor activity, acoustic startle, prepulse inhibition of acoustic startle, and body temperature. Ethanol-induced durations of loss of righting reflex and ethanol elimination rates were also determined. These studies used null mutant (,7,/,) and wild-type (,7+/+) mice. Results: Relative to ,7+/+ mice, ,7,/, mice were more sensitive to the activating effects of ethanol on open-field activity, ethanol-induced hypothermia, and duration of loss of the righting response. Deletion of the ,7 gene did not influence the effects of ethanol on Y-maze crossing or rearing activities, acoustic startle, or prepulse inhibition of startle. Gene deletion did not alter ethanol metabolism. Conclusions: These results indicate that some but not all of the behavioral effects of ethanol are mediated in part by effects on nAChRs that include the ,7 subunit and may help to explain the robust association between alcohol consumption and the use of tobacco. [source]

Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons

THE JOURNAL OF PHYSIOLOGY, Issue 2 2009
Kechun Yang
Dopaminergic (DAergic) neuronal activity in the ventral tegmental area (VTA) is thought to contribute generally to pleasure, reward, and drug reinforcement and has been implicated in nicotine dependence. nAChRs expressed in the VTA exhibit diverse subunit compositions, but the functional and pharmacological properties are largely unknown. Here, using patch-clamp recordings in single DAergic neurons freshly dissociated from rat VTA, we clarified three functional subtypes of nAChRs (termed ID, IID and IIID receptors) based on whole-cell current kinetics and pharmacology. Kinetic analysis demonstrated that comparing to ID, IID receptor-mediated current had faster activation and decay constant and IIID receptor-mediated current had larger current density. Pharmacologically, ID receptor-mediated current was sensitive to the ,4,2-nAChR agonist RJR-2403 and antagonist dihydro-,-erythroidine (DH,E); IID receptor-mediated current was sensitive to the selective ,7-nAChR agonist choline and antagonist methyllycaconitine (MLA); while IIID receptor-mediated current was sensitive to the ,4-containing nAChR agonist cytisine and antagonist mecamylamine (MEC). The agonist concentration,response relationships demonstrated that IID receptor-mediated current exhibited the highest EC50 value compared to ID and IIID receptors, suggesting a relatively low agonist affinity of type IID receptors. These results suggest that the type ID, IID and IIID nAChR-mediated currents are predominately mediated by activation of ,4,2-nAChR, ,7-nAChR and a novel nAChR subtype(s), respectively. Collectively, these findings indicate that the VTA DAergic neurons express diversity and multiplicity of functional nAChR subtypes. Interestingly, each DAergic neuron predominantly expresses only one particularly functional nAChR subtype, which may have distinct but important roles in regulation of VTA DA neuronal function, DA transmission and nicotine dependence. [source]

RIC-3: a nicotinic acetylcholine receptor chaperone

BRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2008
N S Millar
RIC-3 is a transmembrane protein which acts as a molecular chaperone of nicotinic acetylcholine receptors (nAChRs). For some nAChR subtypes (such as homomeric ,7 neuronal nAChRs), RIC-3 is required for efficient receptor folding, assembly and functional expression. In contrast, for other nAChR subtypes (such as heteromeric ,4,2 neuronal nAChRs) there have been reports that RIC-3 can both enhance and reduce levels of functional expression. There is also evidence that RIC-3 can modulate maturation of the closely related 5-hydroxytryptamine (5-HT) receptor (5-HT3R). As with heteromeric nAChRs, apparently contradictory results have been reported for the influence of RIC-3 on 5-HT3R maturation in different expression systems. Recent evidence indicates that these differences in RIC-3 chaperone activity may be influenced by the host cell, suggesting that other proteins may play an important role in modulating the effects of RIC-3 as a chaperone. RIC-3 was originally identified in the nematode Caenorhabditis elegans as the protein encoded by the gene ric-3 (resistance to inhibitors of cholinesterase) and has subsequently been cloned and characterized from mammalian and insect species. This review provides a brief history of RIC-3; from the identification of the ric-3 gene in C. elegans in 1995 to the more recent demonstration of its activity as a nAChR chaperone. British Journal of Pharmacology (2008) 153, S177,S183; doi:10.1038/sj.bjp.0707661; published online 4 February 2008 [source]

Region-specific effects of N,N,-dodecane-1,12-diyl-bis-3-picolinium dibromide on nicotine-induced increase in extracellular dopamine in vivo

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2008
S Rahman
Background and purpose: Systemic administration of N,N,-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), an antagonist of nicotinic acetylcholine receptors (nAChRs) attenuated the nicotine-induced increase in dopamine levels in nucleus accumbens (NAcc). Experimental approach: Using in vivo microdialysis, we investigated the effects of local perfusion of the novel nAChR antagonist bPiDDB into the NAcc or ventral tegmental area (VTA) on increased extracellular dopamine in NAcc, induced by systemic nicotine. We also examined the concentration-dependent effects of bPiDDB on the acetylcholine (ACh)-evoked response of specific recombinant neuronal nAChR subtypes expressed in Xenopus oocytes, using electrophysiological methods. Key results: Nicotine (0.4 mg kg,1, s.c.) increased extracellular dopamine in NAcc, which was attenuated by intra-VTA perfusion of mecamylamine (100 ,M). Intra-VTA perfusion of bPiDDB (1 and 10 ,M) reduced nicotine-induced increases in extracellular dopamine in NAcc. In contrast, intra-NAcc perfusion of bPiDDB (1 or 10 ,M) failed to alter the nicotine-induced increase in dopamine in NAcc. Intra-VTA perfusion of bPiDDB alone did not alter basal dopamine levels, compared to control, nor the increased dopamine in NAcc following amphetamine (0.5 mg kg,1, s.c.). Using Xenopus oocytes, bPiDDB (0.01,100 ,M) inhibited the response to ACh on specific combinations of rat neuronal nAChR subunits, with highest potency at ,3,4,3 and lowest potency at ,6/3,2,3. Conclusions and implications: bPiDDB-Sensitive nAChRs involved in regulating nicotine-induced dopamine release are located in the VTA, rather than in the NAcc. As bPiDDB has properties different from the prototypical nAChR antagonist mecamylamine, further development may lead to novel nAChR antagonists for the treatment of tobacco dependence. British Journal of Pharmacology (2008) 153, 792,804; doi:10.1038/sj.bjp.0707612; published online 3 December 2007 [source]