Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA.
Paris Saclay Institute of Neuroscience, 91440 Saclay, France.
Int J Mol Sci. 2024 Jun 22;25(13):6875. doi: 10.3390/ijms25136875.
Enhanced electrical activity in detrusor smooth muscle (DSM) cells is a key factor in detrusor overactivity which causes overactive bladder pathological disorders. Transient receptor potential melastatin-4 (TRPM4) channels, which are calcium-activated cation channels, play a role in regulating DSM electrical activities. These channels likely contribute to depolarizing the DSM cell membrane, leading to bladder overactivity. Our research focuses on understanding TRPM4 channel function in the DSM cells of mice, using computational modeling. We aimed to create a detailed computational model of the TRPM4 channel based on existing electrophysiological data. We employed a modified Hodgkin-Huxley model with an incorporated TRP-like current to simulate action potential firing in response to current and synaptic stimulus inputs. Validation against experimental data showed close agreement with our simulations. Our model is the first to analyze the TRPM4 channel's role in DSM electrical activity, potentially revealing insights into bladder overactivity. In conclusion, TRPM4 channels are pivotal in regulating human DSM function, and TRPM4 channel inhibitors could be promising targets for treating overactive bladder.
逼尿肌平滑肌（DSM）细胞的电活动增强是导致膀胱过度活动症的关键因素，而膀胱过度活动症会引起膀胱病理紊乱。瞬时受体电位 melastatin-4（TRPM4）通道是一种钙激活阳离子通道，在调节 DSM 电活动中发挥作用。这些通道可能有助于使 DSM 细胞膜去极化，导致膀胱过度活动。我们的研究重点是使用计算建模来了解小鼠 DSM 细胞中的 TRPM4 通道功能。我们旨在根据现有的电生理数据创建一个详细的 TRPM4 通道计算模型。我们采用了一种改良的 Hodgkin-Huxley 模型，其中包含一个整合的 TRP 样电流，以模拟动作电位的发射对电流和突触刺激输入的反应。与实验数据的验证表明，我们的模拟与实验数据非常吻合。我们的模型首次分析了 TRPM4 通道在 DSM 电活动中的作用，这可能为膀胱过度活动症提供新的见解。总之，TRPM4 通道在调节人体 DSM 功能中起着关键作用，TRPM4 通道抑制剂可能是治疗膀胱过度活动症的有前途的靶点。
