Alternative titles; symbols
HGNC Approved Gene Symbol: CHRNB2
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:154,567,778-154,580,013 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | Epilepsy, nocturnal frontal lobe, 3 | 605375 | 3 |
The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be heteropentamers composed of homologous subunits. See 118508 for additional background information on nAChRs.
Anand and Lindstrom (1990) isolated the beta-2 nAChR subunit by screening human fetal brain cDNA libraries with chicken beta-2 as a probe. The predicted 501-amino acid protein has a putative 25-amino acid signal peptide, and is 95% identical to rat beta-2 protein.
Groot Kormelink and Luyten (1997) also isolated human beta-2 cDNAs from neuroblastoma cell lines and from frontal cortex.
Rempel et al. (1998) determined that the CHRNB2 gene comprises 6 exons and spans approximately 9 kb of genomic DNA from the ATG start codon to the TGA stop codon. Exon 1 contains the 5-prime untranslated region, the ATG start codon, and parts of the sequence coding for the putative signal peptide. The hydrophobic transmembrane domains I through III are located in the large exon 5. Exon 6 contains the transmembrane domain IV as well as the translation stop codon and the 3-prime untranslated region. The CHRNB2 introns vary in size from 150 bp (intron 2) to 4.5 kb (intron 5). The splicing at the junctions of CHRNB2 introns 2, 3, and 5 occurred between codons (splicing type 0). Introns 1 and 4 were spliced after the first base (splicing type 1) and the second base of the codon (splicing type 2), respectively.
Elliott et al. (1996) demonstrated that human beta-2 encodes a functional receptor when expressed in combination with human alpha-2 (CHRNA2; 118502), alpha-3 (CHRNA3; 118503), or alpha-4 (CHRNA4; 118504) in Xenopus oocytes.
By immunoprecipitation analysis of mouse striatal extracts, Champtiaux et al. (2003) identified 3 main types of heteromeric nAChRs: alpha-4/beta-2, alpha-6 (CHRNA6; 606888)/beta-2, and alpha-4/alpha-6/beta-2. Alpha-6/beta-2 nAChRs were mainly located on dopamine (DA) nerve terminals and were the direct target of alpha-conotoxin MII inhibition. A combination of alpha-6/beta-2 and alpha-4/beta-2 nAChRs mediated endogenous cholinergic modulation of DA release induced by systemic nicotine administration at nerve terminals. Alpha-4/beta-2 nAChRs appeared to represent the majority of nAChRs on DA neuron soma and contributed to nicotine reinforcement.
Maskos et al. (2005) reexpressed the beta-2 subunit of the nicotinic acetylcholine receptor by stereotaxically injecting a lentiviral vector into the ventral tegmental area of mice carrying beta-2 subunit deletions. Maskos et al. (2005) demonstrated the efficient reexpression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in DA-containing neurons of the ventral tegmental area, together with the recovery of nicotine-elicited DA release and nicotine self-administration. Maskos et al. (2005) also quantified exploratory behaviors of the mice, and showed that beta-2 subunit reexpression restored slow exploratory behavior (a measure of cognitive function) to wildtype levels, but did not affect fast navigation behavior. Maskos et al. (2005) concluded that their data demonstrated the sufficient role of the ventral tegmental area in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.
Crystal Structure
Xiu et al. (2009) showed that at the brain acetylcholine receptors alpha-4-beta-2 thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation-pi interaction to a specific aromatic amino acid of the receptor, TrpB. In contrast, the low affinity for nicotine at the muscle-type acetylcholine receptor is largely due to the absence of this key interaction, even though the immediate binding site residues, including the key amino acid TrpB, are identical in the brain and muscle receptors. At the same time a hydrogen bond from nicotine to the backbone carbonyl of TrpB is enhanced in the neuronal receptor relative to the muscle type. A point mutation near TrpB that differentiates alpha-4-beta-2 and muscle-type receptors seems to influence the shape of the binding site, allowing nicotine to interact more strongly with TrpB in the neuronal receptor.
Cryoelectron Microscopy
Walsh et al. (2018) used cryoelectron microscopy to obtain structures for the alpha-4 (CHRNA4; 118504)-beta-2 nicotinic acetylcholine receptor in both the 2-alpha-to-3-beta and 3-alpha-to-2-beta stoichiometries from a single sample. The antibody fragments specific to beta-2 were used to break symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. The results revealed principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacologic properties of the 2 different stoichiometries of this receptor.
By genomic Southern analysis of hamster/human somatic cell hybrid DNAs, Anand and Lindstrom (1992) mapped the gene encoding the beta-2 subunit of the human neuronal nicotinic acetylcholine receptor to chromosome 1. The corresponding gene is located on chromosome 3 in the mouse (Bessis et al., 1990). By fluorescence in situ hybridization, Rempel et al. (1998) narrowed the chromosomal assignment of the CHRNB2 gene to 1q21. Lueders et al. (1999) mapped the CHRNB2 gene to 1q21.3 by the finding of its sequence within a YAC contig.
Clustered attacks of epileptic episodes originating from the frontal lobe during sleep represent the main manifestation of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE, ENFL; 600513). Because of the description of mutations in the CHRNA4 gene, encoding the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor, in a patient with autosomal dominant nocturnal frontal lobe epilepsy, Rempel et al. (1998) were prompted to consider other members of the neuronal nicotinic acetylcholine receptor family as candidates for the same disorder in families that did not link to CHRNA4 and for other idiopathic epilepsies. They found no mutations in the CHRNB2 gene among 8 unrelated patients with a history of nocturnal frontal lobe epilepsy.
Because of the location of the CHRNB2 gene in the region of chromosome 1 where a form of ENFL maps (ENFL3; 605375), De Fusco et al. (2000) sequenced the entire coding region of the gene in patients and found a missense mutation, val287 to leu (V287L; 118507.0001). All affected members of the family and 4 phenotypically normal individuals shared the heterozygous aberrant band, thus confirming the incomplete penetrance (approximately 75%) previously reported in ENFL pedigrees.
Phillips et al. (2001) described a mutation in the CHRNB2 gene in a Scottish family with ENFL3 (118507.0002); the mutation resulted in a different amino acid substitution at the same valine site affected in the family reported by De Fusco et al. (2000).
Picciotto et al. (1995) disrupted the CHRNB2 mouse homolog in embryonic stem (ES) cells to generate 'knockout' mice deficient in this subunit. Homozygous mice were viable, mated normally, and showed no obvious physical deficits. However, their brains showed absence of high-affinity binding sites for nicotine, and electrophysiologic recordings from brain slices showed that thalamic neurons did not respond to nicotine application. Furthermore, behavioral tests demonstrated that nicotine no longer augmented the performance of the deficient mice on passive avoidance, a test of associative memory. Paradoxically, mutant mice were able to perform better than their nonmutant sibs on this task.
Zoli et al. (1999) demonstrated increased age-related neurodegeneration in the beta-2 knockout mice generated by Picciotto et al. (1995). Neuronal hypotrophy, astrogliosis, and microgliosis were limited to specific anatomic regions including CA1 and CA3 fields in the hippocampus and neocortical areas but not the dentate gyrus or the thalamus. The pattern of neuronal atrophy and gliosis corresponded to areas previously shown to be vulnerable to normal aging but did not correspond simply to the pattern of distribution of beta-2 subunits. There were no significant alterations of other cholinergic markers such as acetylcholinesterase, choline transporters, alpha-bungarotoxin binding sites or muscarinic acetylcholine receptors. There was an increase in the level of circulating corticosterone. The authors proposed that the loss of neurons in the CA3 field could be both a cause and an effect of elevated levels of corticosteroids. Older knockout mice were defective in spatial learning tasks, whereas younger knockout mice performed normally.
Marubio et al. (1999) disrupted the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor by homologous recombination and studied homozygous alpha-4-null mice and mice lacking the beta-2 subunit of the nAChR. The homozygous alpha-4 -/- mice no longer expressed high-affinity nicotine binding sites throughout the brain. In addition, both types of mutant mice displayed a reduced antinociceptive effect of nicotine on the hot-plate test and diminished sensitivity to nicotine in the tail-flick test. Patch-clamp recordings revealed that raphe magnus and thalamic neurons no longer responded to nicotine. Marubio et al. (1999) stated that the alpha-4 nAChR subunit, thought to associate with the beta-2 nAChR subunit, is therefore crucial for nicotine-elicited antinociception.
Manfredi et al. (2009) developed and characterized a mouse model of ENFL3 carrying the V287L mutation (118507.0001) of the CHRNB2 gene. Mice expressing mutant receptors showed a spontaneous epileptic phenotype by electroencephalography with very frequent interictal spikes and seizures. Expression of the mutant protein was driven by a neuronal-specific tetracycline-controlled promoter, which allowed reversible planned silencing of transgene expression. Restricted silencing during development was sufficient to prevent the occurrence of epileptic seizures in adulthood. Manfredi et al. (2009) hypothesized that mutant nicotinic receptors are responsible for abnormal formation of neuronal circuits and/or long-lasting alteration of network assembly in the developing brain, thus leading to epilepsy.
Guillem et al. (2011) found that mice carrying nAChR beta-2-subunit deletions have impaired attention performance. Efficient lentiviral vector-mediated reexpression of functional beta-2-subunit-containing nAChRs in prefrontal cortex neurons of the prelimbic area completely restored the attentional deficient but did not affect impulsive and motivational behavior. Guillem et al. (2011) concluded that beta-2-subunit expression in the prefrontal cortex is sufficient for endogenous nAChR-mediated cholinergic regulation of attentional performance.
In affected members of an Italian family with nocturnal frontal lobe epilepsy-3 (ENFL3; 605375) reported by Gambardella et al. (2000), De Fusco et al. (2000) found a heterozygous G-to-C transversion in exon 5 of the CHRNB2 gene, resulting in a val287-to-leu (V287L) substitution.
In affected members of a Scottish family with nocturnal frontal lobe epilepsy-3 (ENFL3; 605375), Phillips et al. (2001) identified a heterozygous G-to-A transition at nucleotide 1025 in the CHRNB2 gene, resulting in a val287-to-met (V287M) substitution within the M2 domain. Codon 287 was also involved in the family reported by De Fusco et al. (2000); see 118507.0001. The mutation is located in an evolutionarily conserved region of the gene. Functional receptors with the V287M mutation were highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity.
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