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Abstract

Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor.

M Gopalakrishnan, L M Monteggia, D J Anderson, E J Molinari, M Piattoni-Kaplan, D Donnelly-Roberts, S P Arneric and J P Sullivan
Journal of Pharmacology and Experimental Therapeutics January 1996, 276 (1) 289-297;
M Gopalakrishnan
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L M Monteggia
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D J Anderson
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E J Molinari
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M Piattoni-Kaplan
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D Donnelly-Roberts
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S P Arneric
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J P Sullivan
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Abstract

(-)-Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (nAChR) has been shown to bind with high affinity to the rodent and avian alpha 4 beta 2 nAChR subtype. This subtype may represent a primary molecular target for some of the beneficial central nervous system effects i.e., cognitive enhancement, anxiolysis, analgesia, neuroprotection, of (-)-nicotine and related ligands. However, a detailed study of the human alpha 4 beta 2 subunit combination has not yet been reported. In this study, we stably coexpressed the human neuronal alpha 4 and beta 2 nAChR subunits in human embryonic kidney (HEK) 293 cells and studied its pharmacological and regulatory properties. [3H]Cytisine bound to stably transfected cells with high affinity (KD value, 0.2 +/- 0.04 nM) and with a Bmax value of 1359 +/- 91 fmol/mg protein. A good correlation (r = 0.98) was observed between binding affinities in transfected cells and in native neuronal preparations for a series of nAChR ligands. 86Rb+ efflux studies showed that stably transfected cells express functional ion channels that are sensitive to blockade by dihydro-beta-erythroidine. (+/-)-Epibatidine, (-)-nicotine, 1,1-dimethyl-4-phenylpiperazinium, (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT-418), acetylcholine and (-)-cytisine stimulated 86Rb+ efflux with EC50 values of 0.02, 3.9, 2.5, 10, 44 and 38 microM, respectively. Treatment of transfected cells with (-)-nicotine for 7 days led to a significant increase in the density of [3H](-)-cytisine binding sites (EC50 = 0.56 microM) and a significant enhancement in the sensitivity of ACh. Specific binding or (-)-nicotine-evoked cation efflux was not detected in untransfected cells. Analysis of total cellular RNA from transfected, but not untransfected cells, showed the expected fragment sizes corresponding to the human alpha 4 and beta 2 subunit mRNA. These results demonstrate that stable expression of the human alpha 4 beta 2 nAChR subunit combination can give rise to functional ion channels that bind [3H](-)-cytisine with high affinity, exhibit homologous regulation and evoke agonist-induced cation flux with pharmacological properties consistent with native neuronal alpha 4 beta 2 nAChR.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 276, Issue 1
1 Jan 1996
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Abstract

Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor.

M Gopalakrishnan, L M Monteggia, D J Anderson, E J Molinari, M Piattoni-Kaplan, D Donnelly-Roberts, S P Arneric and J P Sullivan
Journal of Pharmacology and Experimental Therapeutics January 1, 1996, 276 (1) 289-297;

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Abstract

Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor.

M Gopalakrishnan, L M Monteggia, D J Anderson, E J Molinari, M Piattoni-Kaplan, D Donnelly-Roberts, S P Arneric and J P Sullivan
Journal of Pharmacology and Experimental Therapeutics January 1, 1996, 276 (1) 289-297;
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