The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition

K Siddiquee, J Hampton, D McAnally, Lauren Therese May, Layton H Smith

Research output: Contribution to journalArticleResearchpeer-review

Abstract

BACKGROUND AND PURPOSE: The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease. EXPERIMENTAL APPROACH: The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of beta-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays. KEY RESULTS: Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP(1) ) and beta-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin. CONCLUSIONS AND IMPLICATIONS: Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology. LINKED ARTICLE: This article is commented on by Goupil et al., pp. 1101-1103 of this issue.
Original languageEnglish
Pages (from-to)1104 - 1117
Number of pages14
JournalBritish Journal of Pharmacology
Volume168
Issue number5
DOIs
Publication statusPublished - 2013

Cite this

Siddiquee, K ; Hampton, J ; McAnally, D ; May, Lauren Therese ; Smith, Layton H. / The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. In: British Journal of Pharmacology. 2013 ; Vol. 168, No. 5. pp. 1104 - 1117.
@article{c665b95343b14cf3b1fcaf6e145babb6,
title = "The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition",
abstract = "BACKGROUND AND PURPOSE: The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease. EXPERIMENTAL APPROACH: The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of beta-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays. KEY RESULTS: Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP(1) ) and beta-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin. CONCLUSIONS AND IMPLICATIONS: Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology. LINKED ARTICLE: This article is commented on by Goupil et al., pp. 1101-1103 of this issue.",
author = "K Siddiquee and J Hampton and D McAnally and May, {Lauren Therese} and Smith, {Layton H}",
year = "2013",
doi = "10.1111/j.1476-5381.2012.02192.x",
language = "English",
volume = "168",
pages = "1104 -- 1117",
journal = "British Journal of Pharmacology",
issn = "1476-5381",
publisher = "Wiley-Blackwell",
number = "5",

}

The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. / Siddiquee, K; Hampton, J; McAnally, D; May, Lauren Therese; Smith, Layton H.

In: British Journal of Pharmacology, Vol. 168, No. 5, 2013, p. 1104 - 1117.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition

AU - Siddiquee, K

AU - Hampton, J

AU - McAnally, D

AU - May, Lauren Therese

AU - Smith, Layton H

PY - 2013

Y1 - 2013

N2 - BACKGROUND AND PURPOSE: The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease. EXPERIMENTAL APPROACH: The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of beta-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays. KEY RESULTS: Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP(1) ) and beta-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin. CONCLUSIONS AND IMPLICATIONS: Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology. LINKED ARTICLE: This article is commented on by Goupil et al., pp. 1101-1103 of this issue.

AB - BACKGROUND AND PURPOSE: The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease. EXPERIMENTAL APPROACH: The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of beta-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays. KEY RESULTS: Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP(1) ) and beta-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin. CONCLUSIONS AND IMPLICATIONS: Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology. LINKED ARTICLE: This article is commented on by Goupil et al., pp. 1101-1103 of this issue.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594671/pdf/bph0168-1104.pdf

U2 - 10.1111/j.1476-5381.2012.02192.x

DO - 10.1111/j.1476-5381.2012.02192.x

M3 - Article

VL - 168

SP - 1104

EP - 1117

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 1476-5381

IS - 5

ER -