Signaling pathways of bradykinin-induced contractions in murine and human detrusor muscle
Mihályi-Borsodi Kinga
Theoretical and Translational Medicine
Dr. Kellermayer Miklós
SE Semmelweis Szalon
2024-10-28 13:00:00
Kórélettan és transzlációs medicina
Dr. Benyó Zoltán
Dr. Benyó Zoltán
Dr. Kaucsár Tamás
Dr. Tóth Balázs István
Dr. Geiszt Miklós
Dr. Sipeki Szabolcs
Dr. Tod Pál
“Signaling pathways of bradykinin-induced contractions in murine and human detrusor muscle”
Our results indicate that BK elicits marked, dose-dependent contractions in both mouse and human
UBSM, which effects are independent of the secondary release of ACh, ATP, or COX-derived
mediators. The receptor preference of BK was also investigated and it was demonstrated that BK
acts predominantly via activating B2 receptors in both species in our experiments. Evaluation of
mouse bladder experiments aiming to assess the downstream signaling of the B2 receptors showed
that the Ca2+
-dependent Gq/11- and the Ca2+
-sensitizing G12/13-pathways both convey the effect of
B2 receptor activation. This sheds light on a unique feature of the UBSM, as BK’s effects are
usually mediated via only the Gq/11 and less frequently through the Gi, G12/13, and Gs proteins. The
role of the ROCK enzyme, which is part of the G12/13 protein-coupled signaling pathway, was also
affirmed in mediating BK-elicited mouse bladder contractions. As BK failed to induce any
contractions in Gαq/11-KO mouse bladders treated with the ROCK inhibitor, Y-27632, it was also
proved that the Gq/11- and the G12/13-coupled pathways exclusively mediate BK’s effects in mouse
UBSM. These pathways were also investigated in contractions evoked by other inflammatory
mediators, namely PGE2 and PGF2α. We proved that the two signaling cascades have an important
role in PG-induced contractions, implying that their further research may be interesting regarding
bladder dysfunctions associated with inflammatory mediators.
The contribution of ROCK enzyme to BK-evoked contractions was demonstrated in human bladder
strips as well, suggesting that ROCK enzyme as well as B2 receptors may provide promising, novel
therapeutic targets for bladder smooth muscle dysfunctions, such as OAB and DO. Nevertheless,
investigating the role of BK in disease models is essential in future studies, as our experiments
were conducted on healthy tissues and BK receptor expression may alter in bladder disorders,
especially in OAB and DO.
