title: Mechanisms of inverse agonism of antipsychotic drugs at the D(2) dopamine receptor: use of a mutant D(2) dopamine receptor that adopts the activated conformation.
abstract: The antipsychotic drugs have been shown to be inverse agonists at the D(2) dopamine receptor. We have examined the mechanism of this inverse agonism by making mutations in residue T343 in the base of the sixth transmembrane spanning region of the receptor. T343R, T343S and T343K mutant D(2) dopamine receptors were made and the T343R mutant characterized in detail. The T343R mutant D(2) dopamine receptor exhibits properties of a receptor that resides more in the activated state, namely increased agonist binding affinity (independent of G-protein coupling and dependent on agonist efficacy), increased agonist potency in functional tests (adenylyl cyclase inhibition) and increased inverse agonist effects. The binding of agonists to the mutant receptor also shows sensitivity to sodium ions, unlike the native receptor, so that isomerization of the receptor to its inactive state may be driven by sodium ions. The binding of inverse agonists to the receptor is, however, unaffected by the mutation. We conclude that inverse agonism at this receptor is not achieved by the inverse agonist binding preferentially to the non-activated state of the receptor over the activated state. Rather the inverse agonist appears to bind to all forms of the receptor but then renders the receptor inactive.
authors: School of Animal and Microbial Sciences, University of Reading, Whiteknights, Reading, UK.
authors: J
authors: J
authors: Wilson
authors: H
authors: H
authors: Lin
authors: D
authors: D
authors: Fu
authors: J A
authors: JA
authors: Javitch
authors: P G
authors: PG
authors: Strange
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000378:metabolism / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001058:Apomorphine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001971:Bromocriptine / Q000378:metabolism / Q000494:pharmacology; D002069:Butaclamol / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D002746:Chlorpromazine / Q000378:metabolism / Q000494:pharmacology; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D046911:Macromolecular Substances; D016297:Mutagenesis, Site-Directed; D010627:Phenethylamines / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D013134:Spiperone / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013469:Sulpiride / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014439:Tyramine / Q000378:metabolism
chemical_list: C425777:10,11-dihydroxy-N-n-propylnorapomorphine; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D046911:Macromolecular Substances; D010627:Phenethylamines; D010880:Piperidines; D017448:Receptors, Dopamine D2; D011993:Recombinant Fusion Proteins; D005576:Colforsin; C029261:phenethylamine; D001971:Bromocriptine; D013134:Spiperone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D013469:Sulpiride; C045971:UH 232; D012964:Sodium; C026539:preclamol; D002069:Butaclamol; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine; D015056:1-Methyl-3-isobutylxanthine; D002746:Chlorpromazine; D014439:Tyramine