PhD Scientific Days 2022

Translational Medicine I. (Poster discussion will take place on the terrace of the room during the Coffee Break)

Intracellular Signaling Pathways of Muscarinic Receptors in Murine Urinary Bladder

Előadó neve

Dr. Balla, Helga

Előadó munkahelye

Institute of Translational Medicine

Előadó telefonszáma

+36301617621

Előadó e-mail címe

balla.helga@phd.semmelweis.hu

Az előadás címe

Intracellular Signaling Pathways of Muscarinic Receptors in Murine Urinary Bladder

Szerző(k) neve és munkahelye

Helga Balla1, Kinga Borsodi1, Petra Őrsy1, Horváth Béla1, Péter József Molnár1,2, Ádám Lénárt1, Éva Ruisanchez1, Stefan Offermans2, Zoltán Benyó1

1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2 Department of Urology, Semmelweis University, Budapest, Hungary
3 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

Bemutatás módja

Szóbeli

Szekció

Translational Medicine I. (Poster discussion will take place on the terrace of the room during the Coffee Break)

Language of the presentation

English

Preferred session

Theoretical and Translational Medicine

Összefoglaló szövege

Overactive bladder (OAB) is a clinical condition with a prevalence of 16% and affects the patients’ quality of life significantly. Currently, antimuscarinic drugs are the first-line medical therapy for the management of OAB. However, their application is limited due to their side-effects.

Our aim was to analyze signaling pathways of muscarinic receptors in detrusor muscle contraction with the goal of better understanding the intracellular regulation of micturition and identifying potential novel therapeutic targets of OAB.

Experiments were performed on adult, male, wild-type (WT), M2, M3, M2/M3, Gαq/11 or Gα12/13 knockout (KO) and pertussis toxin (PTX)-treated mice. Urinary bladder smooth muscle (UBSM) strips were prepared without urothelium under microscope. Contraction force and RhoA activity were measured in the mouse UBSM.

Our results show that contractile responses induced by the muscarinic receptor agonist carbamylcholine (CCh) in UBSM were reduced in the presence of the ROCK inhibitor Y-27632. The CCh-induced contractions were markedly reduced in detrusor strips lacking either M2 or M3 receptors and were completely abolished in UBSM from M2/M3 KO mice. The RhoA activation was significantly decreased in both M2 KO and M3 KO mouse bladders and it was completely diminished in M2/M3 KO UBSM tissues. The concentration-response curve of CCh was shifted to the right in UBSM from mice treated with PTX. The CCh-generated Rho activation was completely abolished in UBSM strips from PTX-treated mice. Detrusor muscle contractions evoked by CCh were further decreased in Gαq/11 KO mice, whereas RhoA activation was unaffected in Gαq/11 KO animals compared to controls.

We concluded that the RhoA-ROCK pathway plays an essential role in UBSM contractions induced by CCh. Moreover, CCh-induced detrusor contraction and RhoA activation are mediated by both M2 and by M3 receptors. Furthermore, CCh-induced contractions involve simultaneously the classical Gαq/11- and the Gαi-coupled signaling pathways, but the RhoA activation appears to be mediated exclusively by the Gαi/o proteins. The detailed understanding of muscarinic signaling pathways may offer a novel, more specific target in the treatment of OAB.

Funding: Hungarian NRDIO K-112964, K-125174, K-135683 and K-139230, EFOP-3.6.3-VEKOP-16-2017-00009 grants and by Gedeon Richter Plc Talent Foundation.

University and Doctoral School

Semmelweis University, Doctoral School of Theoretical and Translational Medicine

Supervisor

Zoltán Benyó MD, PhD, DSc

Publication of my abstract

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

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

6178

Start

09:45

End

10:00

Authors (legacy)

Helga Balla1, Kinga Borsodi1, Petra Őrsy1, Horváth Béla1, Péter József Molnár1,2, Ádám Lénárt1, Éva Ruisanchez1, Stefan Offermans2, Zoltán Benyó1

1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2 Department of Urology, Semmelweis University, Budapest, Hungary
3 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.