Human α6 AChR subtypes: subunit composition, assembly, and pharmacological responses

Kuryatov, Alexander; Olale, Felix; Cooper, Jay M.; Choi, Catherine H.; Lindstrom, Jon

doi:10.1016/s0028-3908(00)00144-1

Cited by 207 publications

(316 citation statements)

References 33 publications

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“…a-CtxMII is a selective antagonist for a6-nAChRs gate dopamine release in NAc R Exley et al a3/a6*-nAChRs (Cartier et al, 1996;Kuryatov et al, 2000), but since there is negligible presence of the a3-subunit in mouse striatum (Champtiaux et al, 2003;Zoli et al, 2002), a-CtxMII is selective for a6*-nAChRs (Champtiaux et al, 2002;Quik and McIntosh, 2006;Whiteaker et al, 2000). In the striatum, a-CtxMII-sensitive a6*-nAChRs include a6b2b3 and a6a4b2b3-nAChRs (Salminen et al, 2004(Salminen et al, , 2005.…”

Section: Experimental Design and Analysismentioning

confidence: 99%

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

Exley

Clements

Hartung

et al. 2007

Neuropsychopharmacol

227

262

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Modulation of striatal dopamine (DA) neurotransmission plays a fundamental role in the reinforcing and ultimately addictive effects of nicotine. Nicotine, by desensitizing b2 subunit-containing (b2*) nicotinic acetylcholine receptors (nAChRs) on striatal DA axons, significantly enhances how DA is released by reward-related burst activity compared to nonreward-related tonic activity. This action provides a synaptic mechanism for nicotine to facilitate the DA-dependent reinforcement. The subfamily of b2*-nAChRs responsible for these potent synaptic effects could offer a molecular target for therapeutic strategies in nicotine addiction. We explored the role of a6b2*-nAChRs in the nucleus accumbens (NAc) and caudate-putamen (CPu) by observing action potential-dependent DA release from synapses in real-time using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in mouse striatal slices. The a6-specific antagonist a-conotoxin-MII suppressed DA release evoked by single and low-frequency action potentials and concurrently enhanced release by high-frequency bursts in a manner similar to the b2*-selective antagonist dihydro-b-erythroidine (DHbE) in NAc, but less so in CPu. The greater role for a6*-nAChRs in NAc was not due to any confounding regional difference in ACh tone since elevated ACh levels (after the acetylcholinesterase inhibitor ambenonium) had similar outcomes in NAc and CPu. Rather, there appear to be underlying differences in nAChR subtype function in NAc and CPu. In summary, we reveal that a6b2*-nAChRs dominate the effects of nicotine on DA release in NAc, whereas in CPu their role is minor alongside other b2*-nAChRs (eg a4*), These data offer new insights to suggest striatal a6*-nAChRs as a molecular target for a therapeutic strategy for nicotine addiction.

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Section: Experimental Design and Analysismentioning

confidence: 99%

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

Exley

Clements

Hartung

et al. 2007

Neuropsychopharmacol

227

262

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“…Several approaches have been applied to overcome this obstacle. First, co-expression of chimeric ␣6/␣3 or ␣6/␣4 subunits (␣6-NTD fused with ␣3-or ␣4-TMD/ICL) with ␤2, ␤2␤3, and ␤4 subunits results in formation of functional receptors in both mammalian cells and oocytes (22)(23)(24)(25)(26)(27). Second, the minute responses observed for ␣6␤2␤3 and ␣6␤4␤3 nAChRs in oocytes have been found to be dramatically enhanced by the introduction of a ␤3 V273S mutant in the receptors (28,29).…”

mentioning

confidence: 99%

Elucidation of Molecular Impediments in the α6 Subunit for in Vitro Expression of Functional α6β4* Nicotinic Acetylcholine Receptors

Jensen

Hoestgaard-Jensen

Jensen

2013

Journal of Biological Chemistry

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Background: Inefficient functional receptor expression in heterologous expression systems has hampered investigations of ␣6* nAChRs. Results: Determinants in the ␣6 subunit for ␣6␤4* functionality have been delineated. Conclusion: Phe 223 and the intracellular loop in ␣6 are molecular impediments to functional ␣6␤4* nAChR expression in vitro. Significance: The molecular basis for the inefficient functional expression of ␣6␤4* nAChRs in vitro has been elucidated.

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“…Results from a comprehensive molecular genetics study in which an individual subunit gene (i.e., α4, α5, α7, β2, β3, and β4) was deleted suggested that at least 6 different subtypes mediate nicotine-evoked DA release from mouse striatal synaptosomes, including 2 classes of nAChRs: α-CtxMII-sensitive nAChRs (i.e., α6β2β3*, α4α6β2β3* and possibly a small amount of α6β2* or α4α6β2* subtypes) and α-CtxMIIresistant nAChRs (i.e., α4β2* and α4α5β2* subtypes), whereas deletion of β4 and α7 subunits had no effect [39]. Also, α6-and β3-containing nAChRs have been implicated in nicotineevoked DA release [24,40,41]. Additionally, substantia nigra neurons express high levels of both α6 and β3 mRNA [26,[40][41][42][43] consistent with their involvement in mediating nicotineevoked DA release.…”

Section: Introductionmentioning

confidence: 98%

“…Genes for α2-α7 and β2-β4 subunits have been identified in mammalian brain [20,21]. Heteromeric nAChRs exist as combinations of α and β subunits, and variations in subunit compositions contribute to differences in nAChR function and pharmacology [22][23][24]. nAChRs are located on DA cell bodies and terminals, including substantia nigra and striatal terminal fields.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

Dwoskin

Joyce

Zheng

et al. 2007

Biochemical Pharmacology

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Limitations in efficacy and high relapse rates of currently available smoking cessation agents reveal the need for more efficacious pharmacotherapies. One strategy is to develop subtype-selective nicotinic receptor (nAChR) antagonists that inhibit nicotine-evoked dopamine (DA) release, the primary neurotransmitter involved in nicotine reward. Simple alkylation of the pyridino N-atom converts nicotine from a potent agonist into a potent antagonist. The classical antagonists, hexamethonium and decamethonium, differentiate between peripheral nAChR subtypes. Using a similar approach, we interconnected varying quaternary ammonium moieties with a lipophilic linker to provide N,N′-bis-nicotinium analogs, affording a lead compound, N,N′-dodecyl-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), which inhibited nicotine-evoked DA release and decreased nicotine self-administration. The current work describes a novel compound, 1-(3-picolinium)-12-triethylammonium-dodecane dibromide (TMPD), a hybrid of bPiDDB and decamethonium. TMPD completely inhibited (IC 50 = 500 nM) nicotine-evoked DA release from superfused rat striatal slices, suggesting that TMPD acts as a nAChR antagonist at more than one subtype. TMPD (1 μM) inhibited the response to acetylcholine at α3β4, α4β4, α4β2, and α1β1εδ receptors expressed in Xenopus oocytes. TMPD had a 2-fold higher affinity for the blood-brain barrier choline transporter, suggesting that is brain bioavailable. TMPD did not inhibit the hyperactivity in nicotine sensitized rats, but significantly and specifically decreased nicotine self-administration. Together, the results suggest that TMPD may have the ability to reduce the rewarding effect of nicotine with minimal side effects, a pharmacological profile indicative of potential clinical utility for the treatment of tobacco dependence.

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Human α6 AChR subtypes: subunit composition, assembly, and pharmacological responses

Cited by 207 publications

References 33 publications

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

Elucidation of Molecular Impediments in the α6 Subunit for in Vitro Expression of Functional α6β4* Nicotinic Acetylcholine Receptors

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

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