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Research ArticleArticle

Using Molecular Tools to Dissect the Role of Gαs in Sensitization of AC1

Timothy A. Vortherms, Chau H. Nguyen, Catherine H. Berlot and Val J. Watts
Molecular Pharmacology December 2004, 66 (6) 1617-1624; DOI: https://doi.org/10.1124/mol.104.000166
Timothy A. Vortherms
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Chau H. Nguyen
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Catherine H. Berlot
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Val J. Watts
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Abstract

Short-term activation of Gαi/o-coupled receptors inhibits adenylyl cyclase, whereas persistent activation of Gαi/o-coupled receptors results in a compensatory sensitization of adenylyl cyclase activity after subsequent activation by Gαs or forskolin. Several indirect observations have suggested the involvement of increased Gαs-adenylyl cyclase interactions in the expression of sensitization; however, evidence supporting a direct role for Gαs has not been well established. In the present report, we used two genetic approaches to further examine the role of Gαs in heterologous sensitization of Ca2+-sensitive type 1 adenylyl cyclase (AC1). In the first approach, we constructed Gαs-insensitive mutants of AC1 (F293L and Y973S) that retained sensitivity to Ca2+ and forskolin activation. Persistent (2 h) activation of the D2 dopamine receptor resulted in a significant augmentation of basal or Ca2+- and forskolin-stimulated AC1 activity; however, sensitization of Gαs-insensitive mutants of AC1 was markedly reduced compared with wild-type AC1. In the second strategy, we examined the requirement of an intact receptor-Gαs signaling pathway for the expression of sensitization using dominant-negative Gαs mutants (α3β5 G226A/A366S or α3β5 G226A/E268A/A366S) to disrupt D1 dopamine receptor activation of recombinant AC1. D1 dopamine receptor-Gαs signaling was attenuated in the presence of α3β5 G226A/A366S or α3β5 G226A/E268A/A366S, but D2 agonist-induced sensitization of Ca2+-stimulated AC1 activity was not altered. Together, the present findings directly support the hypothesis that the expression of sensitization of AC1 involves Gαs-adenylyl cyclase interactions.

  • Received March 5, 2004.
  • Accepted September 10, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (6)
Molecular Pharmacology
Vol. 66, Issue 6
1 Dec 2004
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Research ArticleArticle

Using Molecular Tools to Dissect the Role of Gαs in Sensitization of AC1

Timothy A. Vortherms, Chau H. Nguyen, Catherine H. Berlot and Val J. Watts
Molecular Pharmacology December 1, 2004, 66 (6) 1617-1624; DOI: https://doi.org/10.1124/mol.104.000166

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Research ArticleArticle

Using Molecular Tools to Dissect the Role of Gαs in Sensitization of AC1

Timothy A. Vortherms, Chau H. Nguyen, Catherine H. Berlot and Val J. Watts
Molecular Pharmacology December 1, 2004, 66 (6) 1617-1624; DOI: https://doi.org/10.1124/mol.104.000166
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