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Titolo:
AGONISTS AND ANTAGONISTS DIFFERENTIALLY REGULATE THE HIGH-AFFINITY STATE OF THE D2(L) RECEPTOR IN HUMAN EMBRYONIC KIDNEY 293-CELLS
Autore:
BOUNDY VA; PACHECO MA; GUAN W; MOLINOFF PB;
Indirizzi:
BRISTOL MYERS SQUIBB CO,PHARMACEUT RES INST,CENT NERVOUS SYST DRUG DISCOVERY,5 RES PKWY WALLINGFORD CT 06492 BRISTOL MYERS SQUIBB CO,PHARMACEUT RES INST,CENT NERVOUS SYST DRUG DISCOVERY WALLINGFORD CT 06492 UNIV PENN,SCH MED,DEPT PHARMACOL PHILADELPHIA PA 19104
Titolo Testata:
Molecular pharmacology
fascicolo: 5, volume: 48, anno: 1995,
pagine: 956 - 964
SICI:
0026-895X(1995)48:5<956:AAADRT>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
D2 DOPAMINE RECEPTOR; MOLECULAR-CLONING; PROMOTED DESENSITIZATION; D3-DOPAMINE RECEPTOR; CAUDATE-NUCLEUS; P11 CELLS; EXPRESSION; GENE; RAT; D1;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
44
Recensione:
Indirizzi per estratti:
Citazione:
V.A. Boundy et al., "AGONISTS AND ANTAGONISTS DIFFERENTIALLY REGULATE THE HIGH-AFFINITY STATE OF THE D2(L) RECEPTOR IN HUMAN EMBRYONIC KIDNEY 293-CELLS", Molecular pharmacology, 48(5), 1995, pp. 956-964

Abstract

Studies with radiolabeled antagonists have revealed that both agonists and antagonists induce up-regulation of D2 dopamine receptors in cells transfected to express D2(L) or D2(S) receptors. The regulation induced by agonists, but not antagonists, was synergistic with cAMP analogues, and differences in the time courses of the effects of agonists and antagonists have been observed. These findings have been extended by using a radiolabeled agonist to investigate agonist- and antagonist-induced regulation of the high affinity state of the D2(L) dopamine receptor in transfected HEK 293 cells. Exposure to agonists decreased the proportion of receptors in the high affinity, agonist-preferring state. Exposure to antagonists, however, led to an increase in the density of receptors with a high affinity for agonists. The effects of both agonists and antagonists on the agonist-preferring receptors occurred without a lag and were time and dose dependent. Inhibition of forskolin-stimulated cAMP accumulation by agonists was not affected by exposure of the cells to the antagonist (-)-sulpiride. Desensitization was seen after exposing cells to the agonist quinpirole for 1.5 hr, suggesting that the rapid loss of high affinity binding sites represents an uncoupling of the receptor from the G protein that mediates inhibition of adenylyl cyclase. Pretreatment of cells with the protein synthesis inhibitor cycloheximide did not block the quinpirole-induced loss of receptors with a high affinity for agonists. The effect of (-)-sulpirideon high affinity binding sites was blocked by cycloheximide, but onlyafter incubation of cells for sufficient time to induce an increase in the total number of receptors. After incubation of cells with (-)-sulpiride for a short time, the increase in the number of receptors witha high affinity for agonists was unaffected by cycloheximide. These results suggest that the increase in agonist binding after brief exposure to an antagonist is due to interactions of the receptor with one ormore G proteins that are not coupled to inhibition of adenylyl cyclase, whereas the increase in agonist binding at later time points is associated with the antagonist-induced up-regulation.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 13/07/20 alle ore 07:16:57