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Molecular Pharmacology

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Research ArticleArticle

The Third Intracellular Loop and the Carboxyl Terminus of β2-Adrenergic Receptor Confer Spontaneous Activity of the Receptor

Khalid Chakir, Yang Xiang, Dongmei Yang, Sheng-Jun Zhang, Heping Cheng, Brian K. Kobilka and Rui-Ping Xiao
Molecular Pharmacology November 2003, 64 (5) 1048-1058; DOI: https://doi.org/10.1124/mol.64.5.1048
Khalid Chakir
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Yang Xiang
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Dongmei Yang
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Sheng-Jun Zhang
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Heping Cheng
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Brian K. Kobilka
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Rui-Ping Xiao
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Abstract

It is well established that the β2-adrenergic receptor (β2-AR) exhibits a robust ligand-independent activity, whereas this property is considerably weaker in the closely related β1-AR subtype. To identify the potential domain(s) of β2-AR responsible for the spontaneous receptor activation, we created three chimeras in which the third intracellular loop (β1/β2-Li3) or the carboxyl terminus (β1/β2-CT) or both domains (β1/β2-Li3CT) of β1-AR are replaced by the corresponding parts of the β2-AR. Using adenoviral gene transfer, we individually expressed these β1/β2-AR chimeras in mouse cardiomyocytes lacking both native β1-AR and β2-AR (β1/β2 double knockout), and examined their possible spontaneous activities. Overexpression of these β1/β2-AR chimeras markedly elevated basal cAMP accumulation and myocyte contractility in the absence of agonist stimulation compared with those infected by a control adenovirus expressing β-galactosidase or an adenovirus expressing wild type β1-AR. These effects were fully reversed by a β2-AR inverse agonist, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551; 5 × 10-7 M), regardless of inhibition of Gi with pertussis toxin, but not by a panel of β1-AR antagonists, including [2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2-propanolmethanesulfonate (CGP20712A), betaxolol, bisoprolol, and metoprolol. Furthermore, we have shown that the C-terminal postsynaptic density 95/disc-large/ZO-1 (PDZ) motif of β1-AR is not responsible for the lack of β1-AR spontaneous activation, although it has been known that the β1-AR PDZ motif prevents the receptor from undergoing agonist-induced trafficking and Gi coupling in cardiomyocytes. Taken together, the present results indicate that both the third intracellular loop and the C terminus are involved in β2-AR spontaneous activation and that either domain seems to be sufficient to confer the receptor spontaneous activity.

  • Received April 4, 2003.
  • Accepted July 25, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (5)
Molecular Pharmacology
Vol. 64, Issue 5
1 Nov 2003
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Research ArticleArticle

The Third Intracellular Loop and the Carboxyl Terminus of β2-Adrenergic Receptor Confer Spontaneous Activity of the Receptor

Khalid Chakir, Yang Xiang, Dongmei Yang, Sheng-Jun Zhang, Heping Cheng, Brian K. Kobilka and Rui-Ping Xiao
Molecular Pharmacology November 1, 2003, 64 (5) 1048-1058; DOI: https://doi.org/10.1124/mol.64.5.1048

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Research ArticleArticle

The Third Intracellular Loop and the Carboxyl Terminus of β2-Adrenergic Receptor Confer Spontaneous Activity of the Receptor

Khalid Chakir, Yang Xiang, Dongmei Yang, Sheng-Jun Zhang, Heping Cheng, Brian K. Kobilka and Rui-Ping Xiao
Molecular Pharmacology November 1, 2003, 64 (5) 1048-1058; DOI: https://doi.org/10.1124/mol.64.5.1048
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