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Front. Pharmacol. | doi: 10.3389/fphar.2019.01258

Positive Modulation of Angiotensin II Type 1 Receptor-Mediated Signalling by LVV-Hemorphin-7

 Amanat Ali1, Abdulrasheed Palakkott1, Arshida Ashraf1,  Bincy Baby1,  Ranjit Vijayan1 and  Mohammed Akli AYOUB2*
  • 1Department of Biology, College of Science, United Arab Emirates University, United Arab Emirates
  • 2Department of Biology, College of Science, P.O Box 15551, United Arab Emirates University, United Arab Emirates

Hemorphins are hemoglobin β-chain-derived peptides initially known for their analgesic effects via binding to the opioid receptors belonging to the family of G protein-coupled receptor (GPCR) as well as their physiological action on blood pressure. However, their molecular mechanisms in the regulation of blood pressure are not fully understood. Studies have reported an anti-hypertensive action via the inhibition of the angiotensin-converting enzyme (ACE), a key enzyme in the renin-angiotensin system (RAS). In this study, we hypothesized that hemorphins may also target angiotensin II (AngII) type 1 receptor (AT1R) as a key GPCR in RAS. To investigate this, we examined the effects of LVV-hemorphin-7 on AT1R transiently expressed in human embryonic kidney (HEK293) cells using bioluminescence resonance energy transfer (BRET) technology for the assessment of AT1R/Gαq coupling and β-arrestin 2 recruitment. Interestingly, while LVV-hemorphin-7 alone had no significant effect on BRET signals between AT1R and Gαq or β-arrestin 2, it nicely potentiated AngII-induced BRET signals and significantly increased AngII potency. The BRET data were also correlated with AT1R downstream signalling with LVV-hemorphin-7 potentiating the canonical AngII-mediated Gq-dependent inositol phosphate pathway as well as the activation of the extracellular signal-regulated kinases (ERK1/2). Both AngII and LVV-hemorphin-7-mediated responses were fully abolished by AT1R antagonist demonstrating the targeting of the active conformation of AT1R. Our data report for the first time the targeting and the positive modulation of AT1R signalling by hemorphins, which may explain their role in the physiology and pathophysiology of both vascular and renal systems. This finding further consolidates the pharmacological targeting of GPCRs by hemorphins as previously shown for the opioid receptors in analgesia opening a new era for investigating the role of hemorphins in physiology and pathophysiology via the targeting of GPCR pharmacology and signalling.

Keywords: Hemorphin, AngII, AT1R, GPCR, BRET, RAS-, allosteric modulation., Hypertension

Received: 11 Jul 2019; Accepted: 30 Sep 2019.

Copyright: © 2019 Ali, Palakkott, Ashraf, Baby, Vijayan and AYOUB. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Mohammed Akli AYOUB, United Arab Emirates University, Department of Biology, College of Science, P.O Box 15551, Al-Ain, 37380, United Arab Emirates,