Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy

Abstract

It has recently been demonstrated that the apelin receptor (APJ) plays a significant role in mediating the stretch response within the heart in a G-protein-independent and β-arrestin-dependent fashion. This discovery adds to the consolidated literature describing the potential benefits of APJ agonists. In this review, the authors will examine the functional selectivity of APJ and stretch with respect to their ability to signal via both G-protein-dependent and G-protein-independent mechanisms, with a focus on the multifunctional protein, β-arrestin. The possibility of selecting or designing novel ligands that differentially activate only a subset of functions via a single receptor holds great promise for the treatment of diseases such as heart failure and hypertension. Finally, hypothetical approaches to target APJ, taking into account its downstream pathways, will be described.

Keywords::

• biased ligands
• GPCRs
• pluridimensional efficacy

Financial & competing interests disclosure

This work was supported by R37 HL061690, R01 HL085503, P01 HL091799, P01 HL108806, P01 HL075443, F32 HL110675 awarded to WJ Koch. MC Scimia holds Grants4Targets from Bayer HealthCare, Drug Discovery Initiative from Moulder Center of Temple University, and Scientist Development Grant 14SDG18970045 of the American Heart Association. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Apelin receptor is a multidimensional receptor.

• Biased ligands in the GPCRs field represent a new opportunity for drug discovery.

• Biased ligands selectively targeting pathophysiological pathways may be beneficial for patients suffering from cardiovascular disease.

Notes