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Article: Structure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors

TitleStructure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors
Authors
KeywordsAllosteric regulation
Angiotensin
Bioluminescence resonance energy transfer (BRET)
Calcium
Dimerization
G protein-coupled receptor (GPCR)
Issue Date2016
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2016, v. 291 n. 33, p. 17332-17344 How to Cite?
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 cross-class 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.
Persistent Identifierhttp://hdl.handle.net/10722/232874
ISSN
2019 Impact Factor: 4.238
2015 SCImago Journal Rankings: 3.151
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHarikumar, KG-
dc.contributor.authorAugustine, ML-
dc.contributor.authorLee, LTO-
dc.contributor.authorChow, BKC-
dc.contributor.authorMiller, LJ-
dc.date.accessioned2016-09-20T05:33:05Z-
dc.date.available2016-09-20T05:33:05Z-
dc.date.issued2016-
dc.identifier.citationJournal of Biological Chemistry, 2016, v. 291 n. 33, p. 17332-17344-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10722/232874-
dc.description.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 cross-class 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.-
dc.languageeng-
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/-
dc.relation.ispartofJournal of Biological Chemistry-
dc.subjectAllosteric regulation-
dc.subjectAngiotensin-
dc.subjectBioluminescence resonance energy transfer (BRET)-
dc.subjectCalcium-
dc.subjectDimerization-
dc.subjectG protein-coupled receptor (GPCR)-
dc.titleStructure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors-
dc.typeArticle-
dc.identifier.emailChow, BKC: bkcc@hku.hk-
dc.identifier.authorityChow, BKC=rp00681-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1074/jbc.M116.730754-
dc.identifier.pmid27330080-
dc.identifier.pmcidPMC5016131-
dc.identifier.scopuseid_2-s2.0-84981356892-
dc.identifier.hkuros263791-
dc.identifier.volume291-
dc.identifier.issue33-
dc.identifier.spage17332-
dc.identifier.epage17344-
dc.identifier.isiWOS:000382643800033-
dc.publisher.placeUnited States-

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