Constitutively active Gq/11-coupled receptors enable signaling by co-expressed Gi/o-coupled receptors

被引:41
作者
Bakker, RA [1 ]
Casarosa, P [1 ]
Timmerman, H [1 ]
Smit, MJ [1 ]
Leurs, R [1 ]
机构
[1] Vrije Univ Amsterdam, Div Med Chem, Leiden Amsterdam Ctr Drug Res, NL-1081 HV Amsterdam, Netherlands
关键词
D O I
10.1074/jbc.M309200200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Co-expression of guanine nucleotide-binding regulatory (G) protein-coupled receptors (GPCRs), such as the G(i/o)-coupled human 5-hydroxytryptamine receptor 1B (5-HT1BR), with the G(q/11)-coupled human histamine 1 receptor (H1R) results in an overall increase in agonist-independent signaling, which can be augmented by 5-HT1BR agonists and inhibited by a selective inverse 5-HT1BR agonist. Interestingly, inverse H1R agonists inhibit constitutively H1R-mediated as well as 5-HT1BR agonist-induced signaling in cells co-expressing both receptors. This phenomenon is not solely characteristic of 5-HT1BR; it is also evident with muscarinic M-2 and adenosine A(1) receptors and is mimicked by mastoparan-7, an activator of G(i/o) proteins, or by over-expression of Gbetagamma subunits. Likewise, expression of the G(q/11)-coupled human cytomegalovirus (HCMV)-encoded chemokine receptor US28 unmasks a functional coupling of G(i/o)-coupled CCR1 receptors that is mediated via the constitutive activity of receptor US28. Consequently, constitutively active G(q/11)-coupled receptors, such as the H1R and HCMV-encoded chemokine receptor US28, constitute a regulatory switch for signal transduction by G(i/o)-coupled receptors, which may have profound implications in understanding the role of both constitutive GPCR activity and GPCR cross-talk in physiology as well as in the observed pathophysiology upon HCMV infection.
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收藏
页码:5152 / 5161
页数:10
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