Multiple affinity binding states of the σ receptor: Effect of GTP-binding protein-modifying agents

Y. Itzhak

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


The σ receptor, which is labeled with (+)-[3H]3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [(+)-[3H]3-PPP], is a site that binds several psychotomimetic opiate benzomorphans and certain antipsychotics, such as haloperidol. In order to elucidate the mechanisms involved in σ receptor ligand binding, equilibrium binding analysis and kinetics of association and dissociation of the relatively selective σ receptor ligand (+)-[3H]3-PPP were determined in rat brain membranes in the absence and presence of 5'-guanylylimidodiphosphate [Gpp(NH)p]. In the absence of Gpp(NH)p, (+)-3-PPP, cyclazocine, pentazocine, and (+)-SKF 10047 bind to high and low affinity sites (K(H) = 1.3-7.5 nM; K(L) = 84-500 nM), as determined by computer assisted analysis of the inhibition of (+)-[3H]3-PPP binding by the σ ligands. The antipsychotics haloperidol and chlorpromazine inhibit (+)-[3H]3-PPP binding in a manner indicating interaction with a single state of the receptor. Gpp(NH)p (0.1 mM) abolished the high affinity binding component of the σ agonist-like compounds tested but had no effect on the affinities of the antipsychotics for the receptor. Gpp(NH)p decreased the association rate of (+)-[3H]3-PPP binding 5-fold and also converted the biexponential dissociation kinetics of the ligand, observed in the absence of Gpp(NH)p, to a rapid monophasic dissociation process. Pretreatment of membranes with N-ethylmaleimide and pertussis toxin inhibited (+)-[3H]3-PPP binding and abolished the effect of Gpp(NH)p on the σ ligand binding. These findings indicate that the σ receptor is capable of existing in two discrete states, having high and low affinity for σ agonist-like drugs. The regulation of the high affinity binding state by GTP-binding protein-modifying agents suggests its coupling to GTP-binding protein(s).

Original languageEnglish (US)
Pages (from-to)512-517
Number of pages6
JournalMolecular Pharmacology
Issue number4
StatePublished - Jan 1 1989

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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