Characterization of the recombinant human neuronal nicotinic acetylcholine receptors α3β2 and α4β2 stably expressed in HEK293 cells

Chavez-Noriega, Laura E.; Gillespie, Alison; Stauderman, Kenneth A.; Crona, James H.; Claeps, Brian O'Neil; Elliott, Kathryn; Reid, Richard T.; Rao, Tadimeti S.; Veliçelebi, Gönül; Harpold, Michael M.; Johnson, Edwin C.; Corey-Naeve, Janis

doi:10.1016/s0028-3908(00)00134-9

Cited by 107 publications

(118 citation statements)

References 38 publications

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“…Arguments for the dominant role of the ␤ subunit in desensitization onset kinetics are strengthened by the findings that this characteristic is independent of the type of ␣ subunit expressed (␣3, ␣4, Fenster et al, 1997; ␣6, Kuryatov et al, 2000), whether nicotine or ACh is used (Fenster et al, 1997;Bohler et al, 2001), and despite which cell type is studied . Conversely, in experiments in which the ␤ subunit is kept constant, receptors containing ␣3 subunits desensitize faster than those containing ␣4 (Gross et al, 1991;Vibat et al, 1995;Chavez-Noriega et al, 2000). Thus, overall heteromeric nAChRs can be ordered in terms of their desensitization kinetics (from fastest to slowest): ␣3␤2 Ͼ ␣4␤2 Ͼ ␣3␤4 Ͼ ␣4␤4 (see Fenster et al, 1997).…”

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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“…Some data are also coming from transfected human cell HEK293. j Chavez-Noriega et al (2000). This list is by no means an exhaustive report of all the publications on the subject.…”

Section: Variability In the Sensitivity To Acetycholinementioning

confidence: 99%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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“…Even with the limitations of the IC 50 approach, it is clear that the compound has a marked selectivity for some types of heteromeric receptors. Thus it is a poor antagonist of both α3β4 (IC 50 range 14-23 µM, Chavez-Noriega et al, 1997; and α7 receptors (IC 50 range 2-20 µM, Bertrand et al, 1992;Chavez-Noriega et al, 1997;Virginio et al, 2002). On the other hand, dihydro-β-erythroidine is effective at submicromolar concentrations on recombinant α4β2 and α4β4 receptors (IC 50 values below 0.4 µM, Buisson et al, 1996;Chavez-Noriega et al, 1997;Chavez-Noriega et al, 2000) and is perhaps slightly less potent on α3β2 receptors (IC 50 0.4-1.6 µM; Chavez-Noriega et al, 1997); all these data were obtained at equilibrium, against agonist concentrations between EC 20 and EC 50 , depending on the study).…”

Section: Dihydro-β-erythroidinementioning

confidence: 99%

“…Mecamylamine was originally developed as ganglion blocker and antihypertensive, but, like trimetaphan, its clinical use is now very limited, although it has been suggested as a possible therapeutic agent in Tourette's syndrome. Heterologous expression data show that mecamylamine is not selective for the different receptor types (see for instance Chavez-Noriega et al, 1997;ChavezNoriega et al, 2000), and is effective at low micromolar concentrations. At concentrations greater than 1 µM mecamylamine is an open channel blocker on recombinant α4β2 receptors (Bertrand et al, 1990), and on nicotinic receptors of intracardiac ganglia (Fieber & Adams, 1991) and chromaffin cells (Nooney et al, 1992b;Giniatullin et al, 2000).…”

Section: Mecamylaminementioning

confidence: 99%