The Structures of Neuronal Nicotinic Receptors

Lindstrom, Jon

doi:10.1007/978-3-642-57079-7_6

Cited by 76 publications

(88 citation statements)

References 269 publications

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“…In nicotinic ACh receptors (nAChR) typical a subunits contribute either the whole of the agonist binding domain (Unwin, 2001) or the subsite for the ACh ester moiety (Karlin & Akabas, 1995;Brejc et al, 2001). A typical neuronal a subunit (a2, a3 or a4) will form functional nAChRs when expressed heterologously together with a typical b subunit (b2 or b4; Lindstrom, 2000). These pentameric complexes contain two copies of the a and three copies of the b subunit (Cooper et al, 1991;Boorman et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Formation of functional α3β4α5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach

Groot-Kormelink

Boorman

Sivilotti

2001

British J Pharmacology

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1 The a5 subunit participates to the formation of native neuronal nicotinic receptors, particularly in autonomic ganglia. Like the related b3 subunit, a5 forms functional recombinant receptors if expressed together with a pair of typical a and b subunits, but its e ect on the properties of the resulting aba5 receptor depends on the a and b subunits chosen and on the expression system. We used a reporter mutation approach to test whether a5, like b3, is incorporated as a single copy in human a3b4a5 receptors expressed in oocytes. 2 As previously reported, the main indication of the presence of a5 in a3b4a5 wt was an increase in apparent receptor desensitization (compared with a3b4 receptors). If the a3b4a5 receptor bore a 9'T mutation in the second transmembrane domain of either a3 or b4, a5 incorporation produced a decrease in ACh sensitivity (by 4 fold for a3 LT b4a5 vs a3 LT b4 and by 40 fold for a3b4 LT a5 vs a3b4 LT ). The much greater e ect observed in a3b4 LT a5 receptors accords with the hypothesis that a5 takes the place of a b subunit in the receptor. 3 Introducing a 9'T mutation in a5 had no e ect on the agonist sensitivity of a3b4a5 receptors, but reduced apparent desensitisation, as judged by the sag in the current response to high agonist concentrations. 4 Introducing the 9'T mutation in a3 or b4 in the triplet receptor reduced the EC 50 for ACh by a similar extent (7 and 9 fold, respectively), suggesting that a3b4a5 receptors contain two copies each of a and b and therefore only one copy of a5.

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Section: Introductionmentioning

confidence: 99%

Formation of functional α3β4α5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach

Groot-Kormelink

Boorman

Sivilotti

2001

British J Pharmacology

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“…Some neuronal AChRs, such as the ␣3 AChRs of autonomic ganglia, serve a postsynaptic role in transmission similar to that of muscle AChRs (Lindstrom, 2000b). Both adult autoimmune responses to ␣3 AChRs (Vernino et al, 1998(Vernino et al, , 2000 and rare peri-natal lethal genetic defects in ␣3 AChRs have been reported (Richardson et al, 2001).…”

Section: Neuronal Achr Diseasesmentioning

confidence: 99%

“…Both adult autoimmune responses to ␣3 AChRs (Vernino et al, 1998(Vernino et al, , 2000 and rare peri-natal lethal genetic defects in ␣3 AChRs have been reported (Richardson et al, 2001). Most brain AChRs are thought to modulate the release of transmitters and hormones from presynaptic or preterminal locations (Lindstrom, 2000b). Mutations in both ␣4 and ␤2 subunits have been associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (Steinlein, 2000;DeFusco et al, 2000;Phillips et al, 2001).…”

Section: Neuronal Achr Diseasesmentioning

confidence: 99%

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Autoimmune diseases involving nicotinic receptors

Lindstrom

2002

J. Neurobiol.

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ABSTRACT:The antibody-mediated autoimmune response to ␣1 muscle nicotinic acetylcholine receptors that causes myasthenia gravis is one of the best characterized autoimmune diseases. Antibodymediated autoimmune responses to neuronal nicotinic receptors are just beginning to be discovered and characterized. One of these causes dysautonomia through antibodies to ␣3 nicotinic receptors of autonomic ganglia. Another causes pemphigus through antibodies to ␣9 nicotinic receptors in skin. Other autoimmune responses to nicotinic receptors may be discovered as the many functional roles of nicotinic receptors are revealed.

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“…nAChRs are pentameric and have discrete expression patterns [17][18][19]. 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].…”

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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The Structures of Neuronal Nicotinic Receptors

Cited by 76 publications

References 269 publications

Formation of functional α3β4α5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach

Formation of functional α3β4α5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach

Autoimmune diseases involving nicotinic 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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