PhD Scientific Days 2026

Poster Session 2.C - Molecular Medicine

Investigating Biased Signaling of the AT1 Angiotensin Receptor Using Conformational- and Activation-Based Biosensors

Előadó neve

Dr. Misák, Ádám

Neptune code

NHVSC6

Előadó munkahelye

Department of Physiology, Semmelweis University

Előadó telefonszáma

+36308297793

Előadó e-mail címe

misak.adam@semmelweis.hu

Az előadás címe

Investigating Biased Signaling of the AT1 Angiotensin Receptor Using Conformational- and Activation-Based Biosensors

Szerző(k) neve és munkahelye

Ádám Misák¹, Gábor Turu^1,3, András Dávid Tóth², László Hunyady^1,3

1: Department of Physiology, Semmelweis University
2: Department of Internal Medicine and Haematology, Semmelweis University
3: Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences

Bemutatás módja

Poszter

Szekció

Poster Session 2.C - Molecular Medicine

Language of the presentation

Hungarian

Preferred session

Molecular Medicine

Összefoglaló szövege

Introduction: The angiotensin II type 1 receptor (AT1R) is a key regulator of blood pressure and fluid homeostasis, and it is a major therapeutic target for hypertension and chronic heart failure. Recent research has focused on biased signaling – where ligands selectively activate certain pathways over others – as such agonists may offer therapeutic benefits. However, the mechanism of biased signaling of AT1R remains incompletely understood.
Methods: We have developed a conformation-sensitive nanobody (Nb.AT110i1)-based biosensor. This sensor and a panel of other sensors (mini G protein biosensors, G protein activation and β-arrestin recruitment sensors, and sensors for phosphatidylinositol 4,5-bisphosphate depletion and inositol 1,4,5-trisphosphate production) was transiently transfected in HEK 293T cells. Various AT1R agonists were tested, with angiotensin II (AngII) serving as a reference ligand.
Results: TRV120027, a β-arrestin biased peptide agonist, evoked a several-fold larger BRET ratio increase than AngII for Nb.AT110i1, while both ligands produced comparable BRET ratio increases for β-arrestin2. Furthermore, the small-molecule agonist L-162,313 did not show detectable response when measured with the TRUPATH Gq sensor. Bias signaling analysis showed that TRV120027 is a better activator of the Nb.AT110i1 sensor than AngII, and L-162,313 has a bias profile closely resembling that of a β-arrestin biased ligand.
Conclusion: These findings indicate that Nb.AT110i1 selectively recognizes a receptor conformation enriched by β-arrestin-biased ligands. Such states appear capable of supporting β-arrestin engagement without fully adopting the Gq-activating conformation. Our findings suggest that L-162,313 induces a signaling profile characterized by low Gq/11 activation and maintained β-arrestin recruitment. Hence L-162,313 should be classified as a β-arrestin–biased AT1R agonist with a hitherto unknown mechanism, and may serve as a lead compound for the development of novel non-peptide biased ligands.
Funding: Gedeon Richter Excellence PhD Scholarship, SE 250+ excellence PhD scholarship. Hungarian National Research, Development and Innovation Office grant numbers [NKFI ADVANCED 153452 and 151284, NKFI FK 138862, and TÉT-IPARI Hungarian-Korean grant 2025-1.2.3-TÉT-IPARI-KR-2025-00029].
misak.adam@semmelweis.hu, Semmelweis University, Gábor Turu, András D. Tóth

University

Semmelweis University

Supervisor

Gábor Turu, András Dávid Tóth

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

phd.section.field

after finishing doctoral studies with absolutorium (PhD)

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

7987

Start

18:12

End

18:15