Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase
An agonist-occupied β2-adrenergic receptor (β2-AR) recruits G protein receptor kinase-2 (GRK2) which is recruited to the membrane. Thus, the physical proximity of activated β2-AR and PI-3K allows the activation of the latter. In contrast, it has been observed that the β1-AR is unable to activate the...
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| Format: | Article |
| Language: | English |
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Wiley
2009-01-01
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| Series: | International Journal of Cell Biology |
| Online Access: | http://dx.doi.org/10.1155/2009/959168 |
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| author | Julie Simard Matthieu Boucher Rachel Massé Terence E. Hébert Guy Rousseau |
| author_facet | Julie Simard Matthieu Boucher Rachel Massé Terence E. Hébert Guy Rousseau |
| author_sort | Julie Simard |
| collection | DOAJ |
| description | An agonist-occupied β2-adrenergic receptor (β2-AR) recruits G protein receptor kinase-2 (GRK2) which is recruited to the membrane. Thus, the physical proximity of activated β2-AR and PI-3K allows the activation of the latter. In contrast, it has been observed that the β1-AR is unable to activate the PI-3K/Akt pathway. We hypothesized that the difference might be due to molecular determinants present in the carboxy termini of the two β-AR subtypes. Using transiently transfected HEK 293 cells expressing either β1- or β2-AR, we also observed that in presence of an agonist, β2-AR, but not β1-AR, is able to activate the PI-3K/Akt pathway. Switching the seventh transmembrane domain and the carboxy tail between the two receptors reverses this phenotype; that is, β1×β2-AR can activate the PI-3K/Akt pathway whereas β2×β1-AR cannot. Pretreatment with pertussis toxin abolished the activation of PI-3K by β2- or β1×β2-AR stimulation. Ligand-mediated internalization of the β2-AR induced by a 15-minute stimulation with agonist was abolished in the presence of a dominant negative of PI-3K or following pertussis toxin pretreatment. These results indicate that the subtype-specific differences in the coupling to PI-3K/Akt pathway are due to molecular determinants present in the carboxy tail of the receptor and further that β2-AR activates PI-3K via a pertussis toxin-sensitive mechanism. |
| format | Article |
| id | doaj-art-1797a69a37f14e388e33fc3bbb136abd |
| institution | Kabale University |
| issn | 1687-8876 1687-8884 |
| language | English |
| publishDate | 2009-01-01 |
| publisher | Wiley |
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| series | International Journal of Cell Biology |
| spelling | doaj-art-1797a69a37f14e388e33fc3bbb136abd2025-02-03T05:47:58ZengWileyInternational Journal of Cell Biology1687-88761687-88842009-01-01200910.1155/2009/959168959168Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-KinaseJulie Simard0Matthieu Boucher1Rachel Massé2Terence E. Hébert3Guy Rousseau4Département de Pharmacologie, Université de Montréal, Montréal, PQ, H3C 3J7, CanadaDépartement de Pharmacologie, Université de Montréal, Montréal, PQ, H3C 3J7, CanadaDépartement de Pharmacologie, Université de Montréal, Montréal, PQ, H3C 3J7, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montreal, PQ, H3G 1Y6, CanadaDépartement de Pharmacologie, Université de Montréal, Montréal, PQ, H3C 3J7, CanadaAn agonist-occupied β2-adrenergic receptor (β2-AR) recruits G protein receptor kinase-2 (GRK2) which is recruited to the membrane. Thus, the physical proximity of activated β2-AR and PI-3K allows the activation of the latter. In contrast, it has been observed that the β1-AR is unable to activate the PI-3K/Akt pathway. We hypothesized that the difference might be due to molecular determinants present in the carboxy termini of the two β-AR subtypes. Using transiently transfected HEK 293 cells expressing either β1- or β2-AR, we also observed that in presence of an agonist, β2-AR, but not β1-AR, is able to activate the PI-3K/Akt pathway. Switching the seventh transmembrane domain and the carboxy tail between the two receptors reverses this phenotype; that is, β1×β2-AR can activate the PI-3K/Akt pathway whereas β2×β1-AR cannot. Pretreatment with pertussis toxin abolished the activation of PI-3K by β2- or β1×β2-AR stimulation. Ligand-mediated internalization of the β2-AR induced by a 15-minute stimulation with agonist was abolished in the presence of a dominant negative of PI-3K or following pertussis toxin pretreatment. These results indicate that the subtype-specific differences in the coupling to PI-3K/Akt pathway are due to molecular determinants present in the carboxy tail of the receptor and further that β2-AR activates PI-3K via a pertussis toxin-sensitive mechanism.http://dx.doi.org/10.1155/2009/959168 |
| spellingShingle | Julie Simard Matthieu Boucher Rachel Massé Terence E. Hébert Guy Rousseau Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase International Journal of Cell Biology |
| title | Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase |
| title_full | Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase |
| title_fullStr | Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase |
| title_full_unstemmed | Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase |
| title_short | Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase |
| title_sort | determinants present in the receptor carboxy tail are responsible for differences in subtype specific coupling of β adrenergic receptors to phosphoinositide 3 kinase |
| url | http://dx.doi.org/10.1155/2009/959168 |
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