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Structure and function of Cross-class complexes of G Protein-Coupled secretin and angiotensin 1a receptors
Harikumar K.G.2; Augustine M.L.2; Lee L.T.O.3; Chow B.K.C.1; Miller L.J.2
2016-08-12
Source PublicationJournal of Biological Chemistry
ISSN1083351X 00219258
Volume291Issue:33Pages:17332-17344
AbstractComplexes of secretin (SecR) and angiotensin 1a (Atr1a) receptors have been proposed to be functionally important in osmoregulation, providing an explanation for overlapping and interdependent functions of hormones that bind and activate different classes of GPCRs. However, the nature of these crossclass complexes has not been well characterized and their signaling properties have not been systematically explored. We now use competitive inhibition of receptor bioluminescence resonance energy transfer and bimolecular fluorescence complementation to establish the dominant functionally important state as a symmetrical homodimeric form of SecR decorated by monomeric Atr1a, interacting through lipid-exposed faces of Atr1a TM1 and TM4. Conditions increasing prevalence of this complex exhibited negative allosteric modulatory impact on secretin-stimulated cAMP responses at SecR. In contrast, activating Atr1a with full agonist in such a complex exhibited a positive allosteric modulatory impact on the same signaling event. This modulation was functionally biased, with secretin-stimulated calcium responses unaffected, whereas angiotensin-stimulated calcium responses through the complex were reduced or absent. Further supporting this interpretation, Atr1a with mutations of lipid-exposed faces of TM1 and TM4 that did not affect its ability to bind or signal, could be expressed in the same cell as SecR, yet not exhibit either the negative or positive allosteric impact on cAMP observed with the inactive or activated states of wild type Atr1a on function, and not interfere with angiotensin-stimulated calcium responses like complexes with Atr1a. This may provide a more selective means of exploring the physiologic functional impact of this cross-class receptor complex without interfering with the function of either component receptor.
DOI10.1074/jbc.M116.730754
URLView the original
Language英語
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Cited Times [WOS]:8   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.The University of Hong Kong
2.Mayo Clinic Scottsdale-Phoenix, Arizona
3.Universidade de Macau
Recommended Citation
GB/T 7714
Harikumar K.G.,Augustine M.L.,Lee L.T.O.,et al. Structure and function of Cross-class complexes of G Protein-Coupled secretin and angiotensin 1a receptors[J]. Journal of Biological Chemistry,2016,291(33):17332-17344.
APA Harikumar K.G.,Augustine M.L.,Lee L.T.O.,Chow B.K.C.,&Miller L.J..(2016).Structure and function of Cross-class complexes of G Protein-Coupled secretin and angiotensin 1a receptors.Journal of Biological Chemistry,291(33),17332-17344.
MLA Harikumar K.G.,et al."Structure and function of Cross-class complexes of G Protein-Coupled secretin and angiotensin 1a receptors".Journal of Biological Chemistry 291.33(2016):17332-17344.
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