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Volume 272, Number 52, Issue of December 26, 1997 pp. 32979-32987

Agonist-independent Activation of G_z by the 5-Hydroxytryptamine_1A Receptor Co-expressed in Spodoptera frugiperda Cells
DISTINGUISHING INVERSE AGONISTS FROM NEUTRAL ANTAGONISTS

(Received for publication, July 8, 1997, and in revised form, October 23, 1997)

From the Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084

The human 5-hydroxytryptamine_1A receptor, when expressed in Spodoptera frugiperda (Sf9) cells, facilitates the binding of [³⁵S]GTPS to a co-expressed GTP-binding regulatory protein, G_z, consistent with constitutive activity. The antagonists 4-(2-methoxyphenyl)-1-[2(n-2"-pyridinyl)-p-iodobenzamido]ethyl-piperazine (p-MPPI) and the related fluorobenzamido analogue p-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.

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