Functional domains of the mouse beta3-adrenoceptor associated with differential G-protein coupling

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Abstract

Localization of G-protein-coupled receptors within membrane microdomains is associated with differential signalling pathway activation. We have shown that two mouse beta(3)-AR (beta(3)-adrenoceptor) isoforms encoded by alternatively spliced mRNAs differ in their signalling properties; the beta(3a)-AR couples only with G(s), whereas the beta(3b)-AR couples with both G(s) and G(i). Our previous studies indicated that the beta(3a)-AR is restrained from coupling with G(i) due to the interaction of residues in the C-terminus with other protein(s). We have investigated the hypothesis that the beta(3a)-AR interacts with caveolin. Disruption of caveolae in CHO (Chinese-hamster ovary)-K1 cells expressing wild-type beta(3a)-ARs with filipin III, or mutation of a putative caveolin-binding site in the beta(3a)-AR, causes cAMP accumulation to become PTX (pertussis toxin)-sensitive. Likewise, filipin treatment of mouse brown adipocytes that express endogenous beta(3a)-ARs produces a substantial reduction in agonist-stimulated cAMP production that is rescued by pre-treatment with PTX. These studies suggest that beta(3a)-ARs may be restricted to caveolae and that localization of the receptor may play a specific role in G-protein-mediated signalling.
Original languageEnglish
Pages (from-to)1035 - 1037
Number of pages3
JournalBiochemical Society Transactions
Volume35
Issue numberPt 5
DOIs
Publication statusPublished - 2007

Cite this

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title = "Functional domains of the mouse beta3-adrenoceptor associated with differential G-protein coupling",
abstract = "Localization of G-protein-coupled receptors within membrane microdomains is associated with differential signalling pathway activation. We have shown that two mouse beta(3)-AR (beta(3)-adrenoceptor) isoforms encoded by alternatively spliced mRNAs differ in their signalling properties; the beta(3a)-AR couples only with G(s), whereas the beta(3b)-AR couples with both G(s) and G(i). Our previous studies indicated that the beta(3a)-AR is restrained from coupling with G(i) due to the interaction of residues in the C-terminus with other protein(s). We have investigated the hypothesis that the beta(3a)-AR interacts with caveolin. Disruption of caveolae in CHO (Chinese-hamster ovary)-K1 cells expressing wild-type beta(3a)-ARs with filipin III, or mutation of a putative caveolin-binding site in the beta(3a)-AR, causes cAMP accumulation to become PTX (pertussis toxin)-sensitive. Likewise, filipin treatment of mouse brown adipocytes that express endogenous beta(3a)-ARs produces a substantial reduction in agonist-stimulated cAMP production that is rescued by pre-treatment with PTX. These studies suggest that beta(3a)-ARs may be restricted to caveolae and that localization of the receptor may play a specific role in G-protein-mediated signalling.",
author = "Masaaki Sato and Hutchinson, {Dana Sabine} and Evans, {Bronwyn Anne} and Summers, {Roger James}",
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Functional domains of the mouse beta3-adrenoceptor associated with differential G-protein coupling. / Sato, Masaaki; Hutchinson, Dana Sabine; Evans, Bronwyn Anne; Summers, Roger James.

In: Biochemical Society Transactions, Vol. 35, No. Pt 5, 2007, p. 1035 - 1037.

Research output: Contribution to journalArticleResearchpeer-review

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AB - Localization of G-protein-coupled receptors within membrane microdomains is associated with differential signalling pathway activation. We have shown that two mouse beta(3)-AR (beta(3)-adrenoceptor) isoforms encoded by alternatively spliced mRNAs differ in their signalling properties; the beta(3a)-AR couples only with G(s), whereas the beta(3b)-AR couples with both G(s) and G(i). Our previous studies indicated that the beta(3a)-AR is restrained from coupling with G(i) due to the interaction of residues in the C-terminus with other protein(s). We have investigated the hypothesis that the beta(3a)-AR interacts with caveolin. Disruption of caveolae in CHO (Chinese-hamster ovary)-K1 cells expressing wild-type beta(3a)-ARs with filipin III, or mutation of a putative caveolin-binding site in the beta(3a)-AR, causes cAMP accumulation to become PTX (pertussis toxin)-sensitive. Likewise, filipin treatment of mouse brown adipocytes that express endogenous beta(3a)-ARs produces a substantial reduction in agonist-stimulated cAMP production that is rescued by pre-treatment with PTX. These studies suggest that beta(3a)-ARs may be restricted to caveolae and that localization of the receptor may play a specific role in G-protein-mediated signalling.

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