Oral Presentation ESA-SRB-APEG-NZSE 2022

Novel pharmacology following heteromerisation of the angiotensin II type 2 receptor and the bradykinin type 2 receptor (#122)

Elizabeth KM Johnstone 1 2 3 , Mohammed A Ayoub 1 4 , Rebecca J Hertzman 1 3 , Ruth M Seeber 1 2 , Kevin DG Pfleger 1 2 5
  1. Harry Perkins Institute of Medical Research and Centre for Medical Research, Nedlands, WA, Australia
  2. Australian Research Council Centre for Personalised Therapeutics Technologies, Australia
  3. School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
  4. College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
  5. Dimerix Limited, Nedlands, WA, Australia

Background: Receptor heteromerisation is the phenomenon whereby two different receptors form a functional complex that attains unique pharmacological properties. Consequently, receptor heteromers can be considered novel drug targets, with the potential to achieve greater therapeutic  selectivity and specificity. The angiotensin II type 2 (AT2) receptor and  bradykinin type 2 (B2) receptor are both promising drug targets in their own right (for cardiovascular and other diseases), and the existence of a heteromer that forms between the two could allow improved specificity of targeting. The two receptors have some overlapping pharmacology, such as nitric oxide-mediated vasodilation,  and there is some evidence that observed functional interactions may occur as a result of heteromerization (1).

Aim: Investigation of evidence for heteromerization of the AT2 receptor and the B2 receptor.

Methods: AT2 receptor and B2 receptor pharmacology and potential heteromerisation was investigated in HEK293FT cells using various bioluminescence resonance energy transfer (BRET)-proximity based assays. These assays allow real time, live cell monitoring of proximity between biomolecules of interest, such as receptors and signalling proteins, or receptors and ligands, and therefore produce physiologically relevant, real time pharmacological data.

Results: Heteromerisation of the AT2 receptor and B2 receptor was confirmed with assays showing recruitment of various signalling and regulatory proteins proximal to AT2 receptors only upon B2 receptor coexpression and activation. Additionally, the close proximity between the two receptors was also demonstrated with the NanoBRET ligand-binding assay (2). Attainment of novel pharmacology (Gaz coupling) was observed upon heteromerisation, which did not occur with either receptor alone.

Discussion: Our study has confirmed the heteromerisation of the AT2 receptor and B2 receptor, and showed that this results in the attainment of novel pharmacology. Further studies will aim to reveal the physiological consequences of this heteromerisation.

  1. 1. Abadir PM, Periasamy A, Carey RM, Siragy HM. Angiotensin II Type 2 Receptor–Bradykinin B2 Receptor Functional Heterodimerization. Hypertension. 2006;48(2):316–22.
  2. 2. Johnstone EKM, See HB, Abhayawardana RS, Song A, Rosengren KJ, Hill SJ, et al. Investigation of Receptor Heteromers Using NanoBRET Ligand Binding. Int J Mol Sci. 2021;22(3):1082.