Individual variation in the expression profiles of nicotinic receptors in the olfactory bulb and trigeminal ganglion and identification of α2, α6, α9, and β3 transcripts

Keiger, C. Jane; Walker, Judy

doi:10.1016/s0006-2952(99)00326-3

Cited by 44 publications

(31 citation statements)

References 44 publications

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“…The ␣6 subunit has relatively discrete localization, with expression in catacholaminergic nuclei including the locus coeruleus, the ventral tegmental area, and the substantia nigra (Le Novère et al, 1996;Göldner et al, 1997;Han et al, 2000;Quik et al, 2000;Azam et al, 2002). It is also found in trigeminal ganglion and olfactory bulb (Keiger and Walker, 2000). In addition, ␣6 complexes have been reported in chick retina (Vailati et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Analogs of α-Conotoxin MII Are Selective for α6-Containing Nicotinic Acetylcholine Receptors

et al. 2004

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Neuronal nicotinic acetylcholine receptors (nAChRs) both mediate direct cholinergic synaptic transmission and modulate synaptic transmission by other neurotransmitters. Novel ligands are needed as probes to discriminate among structurally related nAChR subtypes. ␣-Conotoxin MII, a selective ligand that discriminates among a variety of nAChR subtypes, fails to discriminate well between some subtypes containing the closely related ␣3 and ␣6 subunits. Structure-function analysis of ␣-conotoxin MII was performed in an attempt to generate analogs with preference for ␣6-containing [␣6* (asterisks indicate the possible presence of additional subunits)] nAChRs. Alanine substitution resulted in several analogs with decreased activity at ␣3* versus ␣6* nAChRs heterologously expressed in Xenopus laevis oocytes. From the initial analogs, a series of mutations with two alanine substitutions was synthesized. 125 I]␣-conotoxin MII binding to putative ␣6␤2* nAChRs in mouse brain homogenates (K i ϭ 3.3 nM). Thus, structure-function analysis of ␣-conotoxin MII enabled the creation of novel selective antagonists for discriminating among nAChRs containing ␣3 and ␣6 subunits.nAChRs activated by the endogenous neurotransmitter acetylcholine belong to the superfamily of ligand-gated ion channels that also includes GABA A , 5-hydroxytryptamine-3, and glycine receptors (Changeux, 1993). These different ligand-gated ion channels show considerable sequence and structural homology. Each of the subunits has a relatively hydrophilic amino terminal half (ϳ200 amino acids) that constitutes an extracellular domain. This is followed by three hydrophobic transmembrane domains, a large intracellular loop, and then a fourth hydrophobic transmembrane span.A large number of genes have been cloned that encode subunits of nAChRs. It has been proposed that these subunits may be divided into subfamilies on the basis of both gene structure and mature protein sequence. The subunits ␣2, ␣3, ␣4, and ␣6 belong to subfamily III, tribe 1; ␤2 and ␤4 belong to tribe III-2; and the putative structural subunits ␣5 and ␤3 belong to tribe III-3 (Corringer et al., 2000). Within tribe III-1, subunits ␣3 and ␣6 show considerable sequence identity (ϳ80% in the ligand-binding extracellular domain). Thus, designing ligands to distinguish between ␣3* 1 and ␣6* is particularly challenging.␣-Conotoxin MII is a 16 amino acid peptide originally isolated from the venom of the marine snail Conus magus. This peptide potently targets neuronal in preference to the muscle subtype of nicotinic receptor with high affinity for both ␣3␤2 and ␣6* nAChRs. Unfortunately, ␣-conotoxin MII may not distinguish well between ␣3* and ␣6* nAChRs (Kuryatov et al., 2000). In an effort to remedy this situation and produce a selective ligand for ␣6* nAChRs, we have generated a series of ␣-conotoxin MII analogs.The ␣6 subunit is expressed in catecholaminergic neurons and in retina (Le Novère et al., 1996Vailati et al., 1999). In striatum, ␣6* nAChRs seem to play a central role in the modulation ...

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Section: Discussionmentioning

confidence: 99%

Analogs of α-Conotoxin MII Are Selective for α6-Containing Nicotinic Acetylcholine Receptors

et al. 2004

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“…Although nAChRs are widely distributed in the peripheral nervous system (PNS) [28] , no α6 subunit mRNA has been detected in the PNS (ciliary, superior cervical, sympathetic, dorsal root, nodose and petrous ganglia), except in trigeminal nucleus and trigeminal ganglion [26,29] . Thus, we can draw the conclusion that the natural expression of α6*-nAChRs appears to be largely excluded from the PNS and mainly restricted to the CNS, and particularly enriched in midbrain catecholaminergic nuclei.…”

Section: Anatomical Distribution Of α6*-nachrsmentioning

confidence: 99%

Mysterious α6-containing nAChRs: function, pharmacology, and pathophysiology

Yang

Jin

2009

Acta Pharmacol Sin

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Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (α2-α10) and three beta (β2, β3, and β4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although α4β2-and α7-nAChRs are the two major functional nAChR types in the CNS, α6*-nAChRs are abundantly expressed in the midbrain dopaminergic (DAergic) system, including mesocorticolimbic and nigrostriatal pathways, and particularly present in presynaptic nerve terminals. Recently, functional and pharmacological profiles of α6*-nAChRs have been assessed with the use of α6 subunit blockers such as α-conotoxin MII and PIA, and also by using α6 subunit knockout mice. By modulating DA release in the nucleus accumbens (NAc) and modulating GABA release onto DAergic neurons in the ventral tegmental area (VTA), α6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, α6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinson's disease (PD). Thus, α6*-nAChRs may hold promise for future clinical treatment of human disorders, such as nicotine addiction and PD. In this review, we mainly focus on the recent advances in the understanding of α6*-nAChR function, pharmacology and pathophysiology.

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“…All primer pairs except ␣2, ␣5, ␣6, and ␤3 span one or more exons. All nAChR primer sets, except ␣2 and ␣5 (Keiger and Walker, 2000), were designed to be subunit specific, species universal (rat/mouse/human) in our laboratory using DNASTAR software (Lasergene, Madison, WI).…”

Section: Rna Preparation and Reverse Transcriptase (Rt)-pcrmentioning

confidence: 99%

Electrophysiological, Pharmacological, and Molecular Evidence for α7-Nicotinic Acetylcholine Receptors in Rat Midbrain Dopamine Neurons

Wu¹,

George²,

Schroeder³

et al. 2004

J Pharmacol Exp Ther

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Dopamine (DA) neurons located in the mammalian midbrain have been generally implicated in reward and drug reinforcement and more specifically in nicotine dependence. However, roles played by nicotinic acetylcholine receptors, including those composed of ␣7-subunits [␣7-nicotinic acetylcholine receptors (nAChRs)], in modulation of DA signaling and in nicotine dependence are not clearly understood. Although midbrain slice recording has been used previously to identify functional ␣7-nAChRs, these preparations are not optimally designed for extremely rapid and reproducible drug application, and rapidly desensitized, ␣7-nAChRmediated currents may have been underestimated or not detected. Here, we use patch-clamp, whole-cell current recordings from single neurons acutely dissociated from midbrain nuclei and having features of DA neurons to characterize acetylcholineinduced, inward currents that rapidly activate and desensitize, are mimicked by the ␣7-nAChR-selective agonist, choline, blocked by the ␣7-nAChR-selective antagonists, methyllycaconitine and ␣-bungarotoxin, and are similar to those of heterologously expressed, human ␣7-nAChRs. We also use reverse transcriptasepolymerase chain reaction, in situ hybridization, and immunocytochemical staining to demonstrate nAChR ␣7 subunit gene expression as message and protein in the rat substantia nigra pars compacta and ventral tegmental area. Expression of ␣7 subunit message and of ␣7-nAChR-mediated responses is developmentally regulated, with both being absent in samples taken from rats at postnatal day 7, but later becoming present and increasing over the next 2 weeks. Collectively, this electrophysiological, pharmacological, and molecular evidence indicates that nAChR ␣7 subunits and functional ␣7-nAChRs are expressed somatodendritically by midbrain DA neurons, where they may play important physiological roles and contribute to nicotine reinforcement and dependence.

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Individual variation in the expression profiles of nicotinic receptors in the olfactory bulb and trigeminal ganglion and identification of α2, α6, α9, and β3 transcripts

Cited by 44 publications

References 44 publications

Analogs of α-Conotoxin MII Are Selective for α6-Containing Nicotinic Acetylcholine Receptors

Analogs of α-Conotoxin MII Are Selective for α6-Containing Nicotinic Acetylcholine Receptors

Mysterious α6-containing nAChRs: function, pharmacology, and pathophysiology

Electrophysiological, Pharmacological, and Molecular Evidence for α7-Nicotinic Acetylcholine Receptors in Rat Midbrain Dopamine Neurons

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