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Titolo:
DIFFERENTIAL REGULATION OF CAMP-MEDIATED GENE-TRANSCRIPTION BY M1 ANDM4 MUSCARINIC ACETYLCHOLINE-RECEPTORS - PREFERENTIAL COUPLING OF M4 RECEPTORS TO G(I)ALPHA-2
Autore:
MIGEON JC; NATHANSON NM;
Indirizzi:
UNIV WASHINGTON,DEPT PHARMACOL,SJ30 SEATTLE WA 98195 UNIV WASHINGTON,DEPT PHARMACOL,SJ30 SEATTLE WA 98195
Titolo Testata:
The Journal of biological chemistry
fascicolo: 13, volume: 269, anno: 1994,
pagine: 9767 - 9773
SICI:
0021-9258(1994)269:13<9767:DROCGB>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
ADENYLATE-CYCLASE ACTIVITY; RAT OLFACTORY-BULB; DEPENDENT PROTEIN-KINASE; CELL-SPECIFIC EXPRESSION; CYCLIC-AMP ACCUMULATION; GTP-BINDING PROTEIN; NEUROBLASTOMA-CELLS; HYDROLYSIS; CLONING; STIMULATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
43
Recensione:
Indirizzi per estratti:
Citazione:
J.C. Migeon e N.M. Nathanson, "DIFFERENTIAL REGULATION OF CAMP-MEDIATED GENE-TRANSCRIPTION BY M1 ANDM4 MUSCARINIC ACETYLCHOLINE-RECEPTORS - PREFERENTIAL COUPLING OF M4 RECEPTORS TO G(I)ALPHA-2", The Journal of biological chemistry, 269(13), 1994, pp. 9767-9773

Abstract

We have used a luciferase reporter gene under the transcriptional control of a cAMP response element as a sensitive monitor of the regulation by muscarinic acetylcholine receptors (mAChRs) of intracellular cAMP levels and cAMP-regulated gene expression. Treatment with the muscarinic agonist carbachol results in an increase in luciferase activity in JEG-3 cells transiently transfected with mouse ml (8-10-fold) and chick m4 (3-5-fold) mAChRs. Control experiments indicate that these responses are not due to a calcium-mediated pathway and are dependent upona functional protein kinase A. The m1 and m4 responses are not sensitive to pertussus toxin and the m4 response was potentiated by it. Thus, these responses do not result from direct stimulation of adenylate cyclase by betagamma subunits released from pertussis toxin-sensitive G-proteins. Atropine treatment of cells transfected with high levels ofm4 mAChR, but not m1, causes an elevation in basal levels of cAMP response element-mediated luciferase expression in the absence of agonist. This suggests that the m4 receptor is spontaneously active and can cause constitutive inhibition of adenylyl cyclase that is relieved by atropine treatment. Surprisingly, the m4 receptor exhibits little if any agonist-induced inhibition of luciferase expression at either low orhigh levels of receptor expression. JEG-3 cells express G(i)alpha-1 and G(i)alpha-3 but not G(i)alpha-2. Cotransfection of G(i)alpha subunits with m4 demonstrates that the m4 receptor requires G(i)alpha-2 for optimal agonist-mediated inhibition. Even in the presence of G(i)alpha-2, high levels of receptor increased luciferase expression at high concentrations of agonist. Thus, the m4 mAChR can undergo a switch in functional coupling from inhibition to stimulation of adenylyl cyclase. This switch is dependent on the level of receptor expression, the subtypes of G-proteins coexpressed with the receptor, and the concentration of agonist. Furthermore, we demonstrate that the G(i)alpha-2 G-protein alpha subunit preferentially couples the m4 mAChR to inhibition of adenylyl cyclase in JEG-3 cells.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/11/20 alle ore 20:12:16