Nicotinic cholinergic receptor (nAChR) subunit mRNAs are found throughout the brain which suggest... more Nicotinic cholinergic receptor (nAChR) subunit mRNAs are found throughout the brain which suggests that nAChRs may have a widespread influence on brain function and explains why the administration of nicotine to humans or laboratory animals results in a multiplicity of behavioral effects. A minimum of seven different nAChR α subunits and three different nAChR β subunits are expressed in the mammalian brain which could lead to extensive diversity in the types of receptors that are actually produced. Enormous progress has been made in the last few years in identifying the receptor types that are expressed in the mammalian brain, but minimal progress has been made in identifying which behaviors (normal, abnormal, and drug-induced) are modulated by specified receptor subtypes. Our goals are to summarize and critically comment on data showing that genetic strategies have been useful in providing answers to questions related to the function and regulation of brain nAChRs.
Ulcerative colitis is a disease of lifelong non-smokers and ex-smokers. The initial observation w... more Ulcerative colitis is a disease of lifelong non-smokers and ex-smokers. The initial observation was made almost by chance in 1981 and showed that only 8 percent of 230 patients with colitis were current smokers compared with 44 percent of matched controls. Since then, many observations of patient populations both hospital and community based, with controls, have confirmed the finding. A meta-analysis on selected studies showed the relationship to be remarkably consistent in terms of the direction of findings; a comparison of former smokers with life-long non smokers showed a significantly greater risk among former smokers. Patients with colitis who are ex-smokers. usually develop their disease within a few years of cessation of smoking. There is little reliable data on the effect of smoking on activity of disease because of the inherent difficulties in such studies. However, half of a group of 30 patients who were intermittent smokers noted improvement of symptoms over six weeks while smoking twenty cigarettes daily. In attempts to identify the reason for benefit from smoking, nicotine has been tested formally using transdermal nicotine patches in a controlled trial involving 77 patients with active colitis; those given nicotine benefited significantly more than controls. Epidemiological data strongly supports the association of non-smoking with ulcerative colitis. Nicotine is probably the active ingredient responsible for this effect and may be of therapeutic value in active disease or prevention of relapse. Mechanisms responsible for the association remain an enigma but may involve mucosal eicosanoids and intestinal mucus.
As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetic... more As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetics of schizophrenia, GABAA receptor subunit genes are plausible candidate genes for the illness. We undertook a search for sequence variations in the coding region of β1 subunit gene by designing intron‐based primers to amplify its 9 exons. Using single strand conformation polymorphism (SSCP) analysis, we found an exon 9 variant present in 3 of 86 unrelated schizophrenic cases derived from families having at least 2 first degree relatives with schizophrenia. Direct sequencing of the SSCP variant revealed a C→G nucleotide transversion at codon 396 predicting a histidine to glutamine substitution in the β1 peptide. The predicted amino acid substitution occurs at a highly conserved site, 9 residues from a cAMP‐dependent serine phosphorylation consensus sequence. All known GABAA β1 subunit genes including human, bovine, and rat, code for histidine at position 396. Although the variant cosegre...
Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A s... more Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A specific subtype of this receptor family, the alpha7 nicotinic acetylcholine receptor, is thought to be the principal alpha-bungarotoxin (alphaBTX)-binding protein in mammalian brain. Although the expression of this receptor subtype has been characterized in rat, no study has specifically compared the expression of both the alpha7 gene and the localization of BTX binding sites in human brain. Expression of alpha7 mRNA and receptor protein in human postmortem brain tissue was examined by in situ hybridization and [125I]-alpha-bungarotoxin autoradiography, respectively, with particular emphasis on regions associated with sensory processing. Regions with high levels of both alpha7 gene expression and [125I]-alphaBTX binding include the nucleus reticularis of the thalamus, the lateral and medial geniculate bodies, the basilar pontine nucleus, the horizontal limb of the diagonal band of Broca, the nucleus basalis of Meynert, and the inferior olivary nucleus. High-to-moderate levels of alpha7 probe hybridization were also seen in the hippocampus and the cerebral cortex; however, there was a reduced or variable degree of [125I]-alphaBTX binding in these regions compared with the level of probe hybridization. In most brain regions, [125I]-alphaBTX binding was localized to neuronal cell bodies similar in morphology to those that exhibited alpha7 hybridization, suggesting that the high-affinity [125I]-alphaBTX binding sites in the human brain are likely to be principally composed of alpha7 receptor subtypes.
The prevalence of smoking in the mentally ill, particularly in schizophrenic patients, is much hi... more The prevalence of smoking in the mentally ill, particularly in schizophrenic patients, is much higher than in the general population. While smoking demographics are altered in these patients, nicotinic receptors are implicated in the disorder. Nicotine normalizes several sensory processing deficits in schizophrenia, as well as improving cognition and disease symptomatology. Smoking has a large effect on gene expression in human brain, and many genes abnormally expressed in schizophrenic nonsmokers are brought to control levels in schizophrenic smokers. The α7 nicotinic receptor gene, CHRNA7, is genetically linked to the disorder in multiple studies. Deletion of Chrna7 in mice results in several traits found in schizophrenic individuals. The expression of α7nAChRs is decreased in postmortem brain of schizophrenic subjects, as measured by α-bungarotoxin binding. Nicotine binding is also decreased in schizophrenic brain, suggesting that high-affinity nicotinic receptor expression is reduced as well. Regulation of the CHRNA7 gene is complex. Promoter methylation and several transcription factors have been identified that affect transcription. The human CHRNA7 gene is unusual in that it is partially duplicated. The duplicated sequences are expressed with exons from a second partial duplication, forming a new, chimeric gene, CHRFAM7A. The duplicated gene is human specific, not being found in rodents or primates. The duplicated sequences in CHRFAM7A are nearly identical to exons 5–10 of the full-length gene, CHRNA7. Thus, exons 5–10 cannot be accurately queried for CHRNA7 in genome-wide association studies. Further, the duplicated gene product, dupα7, is a dominant negative regulator of α7nAChR function, reducing current in response to acetylcholine application. Functional mutations in the CHRNA7 gene promoter and in CHRFAM7A have been identified and are associated with schizophrenia. Several agonists of the α7nAChR have been identified as possible therapeutic drugs, including DMXB-A and choline. Type II allosteric modulators appear to potentiate function of the human heteromeric receptor, containing both CHRNA7 and CHRFAM7A gene products.
Nicotinic cholinergic receptor (nAChR) subunit mRNAs are found throughout the brain which suggest... more Nicotinic cholinergic receptor (nAChR) subunit mRNAs are found throughout the brain which suggests that nAChRs may have a widespread influence on brain function and explains why the administration of nicotine to humans or laboratory animals results in a multiplicity of behavioral effects. A minimum of seven different nAChR α subunits and three different nAChR β subunits are expressed in the mammalian brain which could lead to extensive diversity in the types of receptors that are actually produced. Enormous progress has been made in the last few years in identifying the receptor types that are expressed in the mammalian brain, but minimal progress has been made in identifying which behaviors (normal, abnormal, and drug-induced) are modulated by specified receptor subtypes. Our goals are to summarize and critically comment on data showing that genetic strategies have been useful in providing answers to questions related to the function and regulation of brain nAChRs.
Ulcerative colitis is a disease of lifelong non-smokers and ex-smokers. The initial observation w... more Ulcerative colitis is a disease of lifelong non-smokers and ex-smokers. The initial observation was made almost by chance in 1981 and showed that only 8 percent of 230 patients with colitis were current smokers compared with 44 percent of matched controls. Since then, many observations of patient populations both hospital and community based, with controls, have confirmed the finding. A meta-analysis on selected studies showed the relationship to be remarkably consistent in terms of the direction of findings; a comparison of former smokers with life-long non smokers showed a significantly greater risk among former smokers. Patients with colitis who are ex-smokers. usually develop their disease within a few years of cessation of smoking. There is little reliable data on the effect of smoking on activity of disease because of the inherent difficulties in such studies. However, half of a group of 30 patients who were intermittent smokers noted improvement of symptoms over six weeks while smoking twenty cigarettes daily. In attempts to identify the reason for benefit from smoking, nicotine has been tested formally using transdermal nicotine patches in a controlled trial involving 77 patients with active colitis; those given nicotine benefited significantly more than controls. Epidemiological data strongly supports the association of non-smoking with ulcerative colitis. Nicotine is probably the active ingredient responsible for this effect and may be of therapeutic value in active disease or prevention of relapse. Mechanisms responsible for the association remain an enigma but may involve mucosal eicosanoids and intestinal mucus.
As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetic... more As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetics of schizophrenia, GABAA receptor subunit genes are plausible candidate genes for the illness. We undertook a search for sequence variations in the coding region of β1 subunit gene by designing intron‐based primers to amplify its 9 exons. Using single strand conformation polymorphism (SSCP) analysis, we found an exon 9 variant present in 3 of 86 unrelated schizophrenic cases derived from families having at least 2 first degree relatives with schizophrenia. Direct sequencing of the SSCP variant revealed a C→G nucleotide transversion at codon 396 predicting a histidine to glutamine substitution in the β1 peptide. The predicted amino acid substitution occurs at a highly conserved site, 9 residues from a cAMP‐dependent serine phosphorylation consensus sequence. All known GABAA β1 subunit genes including human, bovine, and rat, code for histidine at position 396. Although the variant cosegre...
Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A s... more Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A specific subtype of this receptor family, the alpha7 nicotinic acetylcholine receptor, is thought to be the principal alpha-bungarotoxin (alphaBTX)-binding protein in mammalian brain. Although the expression of this receptor subtype has been characterized in rat, no study has specifically compared the expression of both the alpha7 gene and the localization of BTX binding sites in human brain. Expression of alpha7 mRNA and receptor protein in human postmortem brain tissue was examined by in situ hybridization and [125I]-alpha-bungarotoxin autoradiography, respectively, with particular emphasis on regions associated with sensory processing. Regions with high levels of both alpha7 gene expression and [125I]-alphaBTX binding include the nucleus reticularis of the thalamus, the lateral and medial geniculate bodies, the basilar pontine nucleus, the horizontal limb of the diagonal band of Broca, the nucleus basalis of Meynert, and the inferior olivary nucleus. High-to-moderate levels of alpha7 probe hybridization were also seen in the hippocampus and the cerebral cortex; however, there was a reduced or variable degree of [125I]-alphaBTX binding in these regions compared with the level of probe hybridization. In most brain regions, [125I]-alphaBTX binding was localized to neuronal cell bodies similar in morphology to those that exhibited alpha7 hybridization, suggesting that the high-affinity [125I]-alphaBTX binding sites in the human brain are likely to be principally composed of alpha7 receptor subtypes.
The prevalence of smoking in the mentally ill, particularly in schizophrenic patients, is much hi... more The prevalence of smoking in the mentally ill, particularly in schizophrenic patients, is much higher than in the general population. While smoking demographics are altered in these patients, nicotinic receptors are implicated in the disorder. Nicotine normalizes several sensory processing deficits in schizophrenia, as well as improving cognition and disease symptomatology. Smoking has a large effect on gene expression in human brain, and many genes abnormally expressed in schizophrenic nonsmokers are brought to control levels in schizophrenic smokers. The α7 nicotinic receptor gene, CHRNA7, is genetically linked to the disorder in multiple studies. Deletion of Chrna7 in mice results in several traits found in schizophrenic individuals. The expression of α7nAChRs is decreased in postmortem brain of schizophrenic subjects, as measured by α-bungarotoxin binding. Nicotine binding is also decreased in schizophrenic brain, suggesting that high-affinity nicotinic receptor expression is reduced as well. Regulation of the CHRNA7 gene is complex. Promoter methylation and several transcription factors have been identified that affect transcription. The human CHRNA7 gene is unusual in that it is partially duplicated. The duplicated sequences are expressed with exons from a second partial duplication, forming a new, chimeric gene, CHRFAM7A. The duplicated gene is human specific, not being found in rodents or primates. The duplicated sequences in CHRFAM7A are nearly identical to exons 5–10 of the full-length gene, CHRNA7. Thus, exons 5–10 cannot be accurately queried for CHRNA7 in genome-wide association studies. Further, the duplicated gene product, dupα7, is a dominant negative regulator of α7nAChR function, reducing current in response to acetylcholine application. Functional mutations in the CHRNA7 gene promoter and in CHRFAM7A have been identified and are associated with schizophrenia. Several agonists of the α7nAChR have been identified as possible therapeutic drugs, including DMXB-A and choline. Type II allosteric modulators appear to potentiate function of the human heteromeric receptor, containing both CHRNA7 and CHRFAM7A gene products.
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Papers by Sherry Leonard