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.

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 β‐arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays.

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 (IP₁) and β‐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.

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.

This article is commented on by Goupil et al., pp. 1101–1103 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12040