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Agonist-independent activation of Gz by the 5-hydroxytryptamine1A receptor co-expressed in spodoptera frugiperda cells: distinguishing inverse agonists from neutral antagonists

Barr, Alastair J. and Manning, David R. (1997) Agonist-independent activation of Gz by the 5-hydroxytryptamine1A receptor co-expressed in spodoptera frugiperda cells: distinguishing inverse agonists from neutral antagonists. Journal of Biological Chemistry, 272 (52). pp. 32979-32987. ISSN 0021-9258

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Official URL: http://dx.doi.org/10.1074/jbc.272.52.32979

Abstract

The human 5-hydroxytryptamine1Areceptor, when expressed in Spodoptera frugiperda (Sf9) cells, facilitates the binding of [35S]GTPγS to a co-expressed GTP-binding regulatory protein, Gz, consistent with constitutive activity. The antagonists 4-(2′-methoxyphenyl)-1-[2′(n-2"-pyridinyl)-p-iodobenzamido]ethyl-piperazine (p-MPPI) and the related fluorobenzamido analoguep-MPPF had little (p-MPPI) or no (p-MPPF) effect on this activity. In contrast, a third antagonist, the neuroleptic spiperone, produced an almost complete suppression. Thus, using G protein activation as an index of receptor activity, p-MPPF was classified as a neutral antagonist,p-MPPI as a partial inverse agonist, and spiperone as essentially a full inverse agonist. As predicted, spiperone displayed properties consistent with a special form of noncompetitive antagonism when used to displace the agonist [125I]R-(+)-trans-8-hydroxy-2-[N-n-propyl-N-(3′-iodo-2′-propenyl)amino]tetralin. Our data profile Sf9 cells as a unique vehicle for the characterization of inverse agonists, as these cells support a systematic pairing of mammalian receptors and G proteins, quantitative assays of G protein activation, and unambiguously labeled populations of coupled and uncoupled receptors.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:10863
Deposited On:20 Jul 2012 14:10
Last Modified:20 Jul 2012 14:10

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