Rat α3/β4 Subtype of Neuronal Nicotinic Acetylcholine Receptor Stably Expressed in a Transfected Cell Line: Pharmacology of Ligand Binding and Function

Xiao, Yingxian; Meyer, Erin L.; Thompson, Jessica M.; Surin, Alexander; Wroblewski, Jarda T.; Kellar, Kenneth J.

doi:10.1124/mol.54.2.322

Cited by 222 publications

(228 citation statements)

References 31 publications

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“…2). Likewise, it is probable that desensitization of the lower affinity putative ␣3␤4*-nAChRs, as observed in various cells representative of both the autonomic nervous system and CNS (Higgins and Berg, 1988;Oortigiesen and Vijverberg, 1989;Mathie et al, 1990;Khiroug et al, 1997Khiroug et al, , 1998Boyd, 1987;Ifune and Steinbach, 1993;Lester and Dani, 1995), in addition to systems designed to specifically express ␣3␤4 receptors (Cachelin and Jaggi, 1991;Hsu et al, 1996;Fenster et al, 1997;Wang et al, 1998;Xiao et al, 1998), can also be explained in terms of the two-state model, although due to the slower time course of desensitization for ␤4 subunit-containing receptors (see below), the biphasic nature may only be seen clearly during longer agonist applications (e.g., Lester and Dani, 1995). Concentration-dependent analyses of desensitization of presumed native ␣3␤4* nAChRs have estimated the affinity of the desensitized state for nicotine to be Ϸ20 -300 nM (Higgins and Berg, 1988;Lester and Dani, 1995).…”

Section: Heteromeric ␣␤* Receptorsmentioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

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Section: Heteromeric ␣␤* Receptorsmentioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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“…The up-regulation of receptor numbers does not appear to be under transcriptional regulation (Marks et al 1992). Rather, the increases may be related to changes in receptor turnover based on receptor desensitization, subunit composition, secondary structural changes in the receptor, or to modification of the receptor by protein kinases (Peng et al 1994;Baenziger and Chew 1997;Eilers et al 1997;Flores et al 1997;Hsu et al 1997;Xiao et al 1998;Fenster et al 1999).In spite of the high degree of nicotine self-administration in schizophrenics (Lohr and Flynn 1992;Ziedonis et al 1994;de Leon et al 1995), few studies have examined the effect of smoking or neuroleptic treatment on nicotinic receptor regulation in this disease (Dalack et al 1998). It has been suggested that nicotine self-administration in schizophrenics may control a neuronal deficit.…”

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confidence: 99%

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Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia

Breese

2000

Neuropsychopharmacology

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Previous studies have suggested that an abnormality in neuronal nicotinic acetylcholine receptor expression or function may be involved in the neuropathophysiology of schizophrenia. [ 3 H]-nicotine and [ 3 H]-epibatidine binding were compared in postmortem brain from control and schizophrenic subjects with varying smoking histories. In control subjects, increased receptor binding was seen in hippocampus, cortex, and caudate with increasing tobacco use. In contrast, schizophrenic smokers had reduced nicotinic receptor levels in these brain regions compared to control smokers. Chronic haloperidol and nicotine treatment, in the rat, was used to assess neuroleptic effects on receptor up-regulation by nicotine. A significant increase in cortical nicotinic receptors was seen in both nicotine treated as well as haloperidol and nicotine co-treated animals, suggesting that the abnormal regulation of high affinity neuronal nicotinic receptors in schizophrenics followingPrevious studies have shown that high affinity nicotinic receptor numbers increase in the brains of human subjects who smoke (Benwell et al. 1988;Breese et al. 1997a;Court et al. 1998). This increase was shown to be dosedependent, based on the number of cigarettes smoked at death, and was reversible, with binding levels returning to control values in subjects who had quit smoking for at least two months prior to death (Breese et al. 1997a). The up-regulation of receptor numbers does not appear to be under transcriptional regulation (Marks et al. 1992). Rather, the increases may be related to changes in receptor turnover based on receptor desensitization, subunit composition, secondary structural changes in the receptor, or to modification of the receptor by protein kinases (Peng et al. 1994;Baenziger and Chew 1997;Eilers et al. 1997;Flores et al. 1997;Hsu et al. 1997;Xiao et al. 1998;Fenster et al. 1999).In spite of the high degree of nicotine self-administration in schizophrenics (Lohr and Flynn 1992;Ziedonis et al. 1994;de Leon et al. 1995), few studies have examined the effect of smoking or neuroleptic treatment on nicotinic receptor regulation in this disease (Dalack et al. 1998). It has been suggested that nicotine self-administration in schizophrenics may control a neuronal deficit. In this regard, it has been shown that abnormal electro- NO . 4 physiological and eye-tracking deficits can be normalized by cigarette smoking or nicotine administration (Adler et al. 1992(Adler et al. , 1993Olincy et al. 1998). Smoking may also alleviate neuroleptic-induced extrapyramidal side effects (Decina et al. 1990;Goff et al. 1992;Sandyk 1993). Nicotine use increases haloperidol metabolism (Jann et al. 1986;Miller et al. 1990), requiring patients that smoke to take higher doses than non-smoking schizophrenics, often further increasing their smoking behavior (McEvoy et al. 1995). Interestingly, clozapine, which does not induce the motor dysfunctions seen with typical neuroleptics, reduces smoking behavior (George et al. 1995) and normalizes the electrophysiologi...

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“…A eukaryotic expression construct was made using the full-length cDNA of the rat α7 subunit gene (a generous gift from Dr James W PATRICK of Baylor College of Medicine). Transfection of HEK-293 cells, and selection and establishment of stable cell lines were carried out as described previously [27] , with minor modifications. Briefly, transfections were carried out using Lipofectamine 2000 transfection reagent (Invitrogen Corp).…”

Section: Introductionmentioning

confidence: 99%

“…Stably transfected mammalian cell lines heterologously expressing neuronal nAChR subtypes have been powerful tools to study neuronal nAChRs [11,[27][28][29][30][31][32] . Several such cell lines expressing functional α7 nAChRs were successfully established in recent years, including the rat α7 subunit gene expressed in SH-SY5Y human neuroblastoma cells, which also express endogenous nAChR α3, α5, α7, β2, and β4 subunit genes [33] ; the human α7 subunit gene expressed in HEK-293 cells [11] and in SH-EP1 clonal human epithelial cells [34,35] , both of which are devoid of endogenous nAChR subunits; and the rat α7 subunit gene expressed in GH 4 C 1 clonal rat pituitary cells, which endogenously express the rat nAChR β4 subunit gene [36,37] .…”

Section: Introductionmentioning

confidence: 99%

Rat neuronal nicotinic acetylcholine receptors containing α7 subunit: pharmacological properties of ligand binding and function

et al. 2009

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Aim:To compare pharmacological properties of heterologously expressed homomeric α7 nicotinic acetylcholine receptors (α7 nAChRs) with those of native nAChRs containing α7 subunit (α7* nAChRs) in rat hippocampus and cerebral cortex. Methods: We established a stably transfected HEK-293 cell line that expresses homomeric rat α7 nAChRs. We studies ligand binding profiles and functional properties of nAChRs expressed in this cell line and native rat α7* nAChRs in rat hippocampus and cerebral cortex. We used [ 125 I]-α-bungarotoxin to compare ligand binding profiles in these cells with those in rat hippocampus and cerebral cortex. The functional properties of the α7 nAChRs expressed in this cell line were studied using whole-cell current recording. The acetylcholine activated currents were potently blocked by two selective antagonists of α7 nAChRs, α-bungarotoxin (IC 50 =19±2 nmol/L) and methyllycaconitine (IC 50 =100±10 pmol/L). A comparative study of ligand binding profiles, using 13 nicotinic ligands, showed many similarities between the homomeric α7 nAChRs and native α7* receptors in rat brain, but it also revealed several notable differences. Conclusion: This newly established stable cell line should be very useful for studying the properties of homomeric α7 nAChRs and comparing these properties to native α7* nAChRs.

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Rat α3/β4 Subtype of Neuronal Nicotinic Acetylcholine Receptor Stably Expressed in a Transfected Cell Line: Pharmacology of Ligand Binding and Function

Cited by 222 publications

References 31 publications

Desensitization of neuronal nicotinic receptors

Desensitization of neuronal nicotinic receptors

Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia

Rat neuronal nicotinic acetylcholine receptors containing α7 subunit: pharmacological properties of ligand binding and function

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