The role of the rho-rock pathway in the regulation of micturition
Balla Helga
Theoretical and Translational Medicine Division
Dr. Kellermayer Miklós
SE Semmelweis Szalon
2024-10-28 10:00:00
Kórélettan és transzlációs medicina
Dr. Benyó Zoltán
Dr. Benyó Zoltán
Dr. Keszthelyi Márton
Dr. Szentandrássy Norbert
Dr. Urbancsek János
Dr. Sirokmány Gábor
Dr. Tod Pál
The mAChRs play an unquestionable role in the regulation of micturition and antimuscarinic drugs are mainstays for the treatment of the worldwide symptom complex, OAB. Nevertheless, the exact signaling pathway of mAChRs is obscure even though a more detailed understanding of the signal transduction pathway may help to find more specific drug targets with fewer adverse effects for OAB.
Therefore, in the present study, we aimed to analyze the role of the M2 and M3 muscarinic receptors and their corresponding heterotrimeric G proteins (Gi and Gq/11, respectively) in the regulation of detrusor function, concentrating on the interaction with the Rho–ROCK pathway. We demonstrated that the ROCK plays a pivotal role in the detrusor contraction induced by the muscarinic receptor agonist, CCh. Moreover, the CCh-induced contractions and RhoA activation are mediated by both the M2 and the M3 receptors according to the results gained from M2-, M3- and M2/M3-KO animals. In addition, the expression levels of other muscarinic receptors were not altered by the genetic deletion of M2 and M3 receptors indicating that no other muscarinic receptors contribute to the UBSM contraction induced by CCh. Furthermore, pharmacological inhibition of the ROCK enzyme had an additional inhibitory effect on the concentration-response curve of CCh in M2- and M3-KO mice. Interestingly, there was no change in the expression of the ROCK1 enzyme in detrusor muscle from mice deficient in M2 or M3 receptors; however, the ROCK2 enzyme expression was elevated in M2/M3-KO mice suggesting a compensatory upregulation of ROCK in the absence of both receptors. PTX treatment of WT mice shifted the concentration-response curve of CCh to the right parallel with a steep decrease in RhoA activation. The CCh-induced contractions were diminished in Gq/11-KO animals; however, the RhoA activation did not change in mice deficient in Gq/11 compared to that of WT. These results indicate that muscarinic receptor-mediated RhoA activation is not mediated by Gq/11 but rather by Gi.
These observations can support the development of novel, more specific therapeutic targets that can help to improve patient adherence along with better-tailored therapeutic strategies of OAB to maximize patients’ quality of life and cost-effective care.
