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Molecular Pharmacology

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Research ArticleArticle

Desensitization of the Dopamine D1 and D2 Receptor Hetero-Oligomer Mediated Calcium Signal by Agonist Occupancy of Either Receptor

Christopher H. So, Vaneeta Verma, Brian F. O'Dowd and Susan R. George
Molecular Pharmacology August 2007, 72 (2) 450-462; DOI: https://doi.org/10.1124/mol.107.034884
Christopher H. So
Departments of Pharmacology (C.H.S., V.V., B.F.O., S.R.G.) and Medicine (S.R.G.), University of Toronto, Toronto, Ontario, Canada; and the Centre for Addiction and Mental Health, Toronto, Ontario, Canada (B.F.O., S.R.G.)
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Vaneeta Verma
Departments of Pharmacology (C.H.S., V.V., B.F.O., S.R.G.) and Medicine (S.R.G.), University of Toronto, Toronto, Ontario, Canada; and the Centre for Addiction and Mental Health, Toronto, Ontario, Canada (B.F.O., S.R.G.)
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Brian F. O'Dowd
Departments of Pharmacology (C.H.S., V.V., B.F.O., S.R.G.) and Medicine (S.R.G.), University of Toronto, Toronto, Ontario, Canada; and the Centre for Addiction and Mental Health, Toronto, Ontario, Canada (B.F.O., S.R.G.)
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Susan R. George
Departments of Pharmacology (C.H.S., V.V., B.F.O., S.R.G.) and Medicine (S.R.G.), University of Toronto, Toronto, Ontario, Canada; and the Centre for Addiction and Mental Health, Toronto, Ontario, Canada (B.F.O., S.R.G.)
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Abstract

When dopamine D1 and D2 receptors were coactivated in D1-D2 receptor hetero-oligomeric complexes, a novel phospholipase C-mediated calcium signal was generated. In this report, desensitization of this Gq/11-mediated calcium signal was demonstrated by pretreatment with dopamine or with the D1-selective agonist (±)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) or the D2-selective agonist quinpirole. Desensitization of the calcium signal mediated by D1-D2 receptor hetero-oligomers was initiated by agonist occupancy of either receptor subtype even though the signal was generated only by occupancy of both receptors. The efficacy, potency, and rate of calcium signal desensitization by agonist occupancy of the D1 receptor (t½, ∼1 min) was far greater than by the D2 receptor (t½, ∼10 min). Desensitization of the calcium signal was not mediated by depletion of calcium stores or internalization of the hetero-oligomer and was not decreased by inhibiting second messenger-activated kinases. The involvement of G protein-coupled receptor kinases 2 or 3, but not 5 or 6, in the desensitization of the calcium signal was shown, occurring through a phosphorylation independent mechanism. Inhibition of Gi protein function associated with D2 receptors increased D1 receptor-mediated desensitization of the calcium signal, suggesting that cross-talk between the signals mediated by the activation of different G proteins controlled the efficacy of calcium signal desensitization. Together, these results demonstrate the desensitization of a signal mediated only by hetero-oligomerization of two G protein-coupled receptors that was initiated by agonist occupancy of either receptor within the hetero-oligomer, albeit with differences in desensitization profiles observed.

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Molecular Pharmacology: 72 (2)
Molecular Pharmacology
Vol. 72, Issue 2
1 Aug 2007
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Research ArticleArticle

Desensitization of the Dopamine D1 and D2 Receptor Hetero-Oligomer Mediated Calcium Signal by Agonist Occupancy of Either Receptor

Christopher H. So, Vaneeta Verma, Brian F. O'Dowd and Susan R. George
Molecular Pharmacology August 1, 2007, 72 (2) 450-462; DOI: https://doi.org/10.1124/mol.107.034884

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Research ArticleArticle

Desensitization of the Dopamine D1 and D2 Receptor Hetero-Oligomer Mediated Calcium Signal by Agonist Occupancy of Either Receptor

Christopher H. So, Vaneeta Verma, Brian F. O'Dowd and Susan R. George
Molecular Pharmacology August 1, 2007, 72 (2) 450-462; DOI: https://doi.org/10.1124/mol.107.034884
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