Intracellular signaling pathways of muscarinic acetylcholine receptor-mediated detrusor muscle contractions.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-11-01 Epub Date: 2023-09-07 DOI:10.1152/ajprenal.00261.2022
Helga Balla, Kinga Borsodi, Petra Őrsy, Béla Horváth, Péter József Molnár, Ádám Lénárt, Mónika Kosztelnik, Éva Ruisanchez, Jürgen Wess, Stefan Offermanns, Péter Nyirády, Zoltán Benyó
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Abstract

Acetylcholine plays an essential role in the regulation of detrusor muscle contractions, and antimuscarinics are widely used in the management of overactive bladder syndrome. However, several adverse effects limit their application and patients' compliance. Thus, this study aimed to further analyze the signal transduction of M2 and M3 receptors in the murine urinary bladder to eventually find more specific therapeutic targets. Experiments were performed on adult male wild-type, M2, M3, M2/M3, or Gαq/11 knockout (KO), and pertussis toxin (PTX)-treated mice. Contraction force and RhoA activity were measured in the urinary bladder smooth muscle (UBSM). Our results indicate that carbamoylcholine (CCh)-induced contractions were associated with increased activity of RhoA and were reduced in the presence of the Rho-associated kinase (ROCK) inhibitor Y-27632 in UBSM. CCh-evoked contractile responses and RhoA activation were markedly reduced in detrusor strips lacking either M2 or M3 receptors and abolished in M2/M3 KO mice. Inhibition of Gαi-coupled signaling by PTX treatment shifted the concentration-response curve of CCh to the right and diminished RhoA activation. CCh-induced contractile responses were markedly decreased in Gαq/11 KO mice; however, RhoA activation was unaffected. In conclusion, cholinergic detrusor contraction and RhoA activation are mediated by both M2 and M3 receptors. Furthermore, whereas both Gαi and Gαq/11 proteins mediate UBSM contraction, the activation at the RhoA-ROCK pathway appears to be linked specifically to Gαi. These findings may aid the identification of more specific therapeutic targets for bladder dysfunctions.NEW & NOTEWORTHY Muscarinic acetylcholine receptors are of utmost importance in physiological regulation of micturition and also in the development of voiding disorders. We demonstrate that the RhoA-Rho-associated kinase (ROCK) pathway plays a crucial role in contractions induced by cholinergic stimulation in detrusor muscle. Activation of RhoA is mediated by both M2 and M3 receptors as well as by Gi but not Gq/11 proteins. The Gi-RhoA-ROCK pathway may provide a novel therapeutic target for overactive voiding disorders.

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毒蕈碱乙酰胆碱受体介导逼尿肌收缩的细胞内信号通路。
乙酰胆碱在调节逼尿肌收缩中起着重要作用,而抗肌肉毒蕈碱被广泛用于治疗膀胱过度活动综合征。然而,一些不良反应限制了它们的应用和患者的依从性。因此,本研究旨在进一步分析小鼠膀胱中M2和M3受体的信号转导,以最终找到更特异的治疗靶点。实验在成年雄性野生型、M2、M3、M2/M3或Gαq/11敲除(KO)和百日咳毒素(PTX)处理的小鼠上进行。测量膀胱平滑肌(UBSM)的收缩力和RhoA活性。我们的结果表明,在UBSM中,氨甲酰胆碱(CCh)诱导的收缩与RhoA活性的增加有关,并且在存在Rho相关激酶(ROCK)抑制剂Y-27632的情况下减少。CCh诱发的收缩反应和RhoA激活在缺乏M2或M3受体的逼尿肌条中显著减少,在M2/M3 KO小鼠中消失。PTX处理对Gαi偶联信号的抑制使CCh的浓度-反应曲线向右移动,并减少RhoA的激活。αq/11 KO小鼠CCh诱导的收缩反应显著降低;但RhoA的活化不受影响。总之,胆碱能逼尿肌收缩和RhoA激活是由M2和M3受体介导的。此外,尽管Gαi和Gαq/11蛋白都介导UBSM收缩,但RhoA-ROCK途径的激活似乎与Gαi特异性相关。这些发现可能有助于确定膀胱功能障碍的更具体的治疗靶点。新的和值得注意的毒蕈碱乙酰胆碱受体在排尿的生理调节和排尿障碍的发展中至关重要。我们证明了RhoA-Rho相关激酶(ROCK)通路在逼尿肌胆碱能刺激诱导的收缩中起着至关重要的作用。RhoA的激活是由M2和M3受体以及Gi介导的,但不是由Gq/11蛋白介导的。Gi-RoA-ROCK通路可能为过度活动性排尿障碍提供一种新的治疗靶点。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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Sex-specific epigenetic programming in renal fibrosis and inflammation. Why is chronic kidney disease progressive? Evolutionary adaptations and maladaptations. Intracellular signaling pathways of muscarinic acetylcholine receptor-mediated detrusor muscle contractions. Role of the SLC22A17/lipocalin-2 receptor in renal endocytosis of proteins/metalloproteins: a focus on iron- and cadmium-binding proteins. Renal tubular SGK1 is required to achieve blood pressure surge and circadian rhythm.
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