In Silico Electrophysiological Investigation of Transient Receptor Potential Melastatin-4 Ion Channel Biophysics to Study Detrusor Overactivity

Abstract

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.

Keywords: TRPM4 ion channel; action potential; computational modeling; urinary incontinence.

Figure 1

Schematic illustration of the proposed physiological role for TRPM4 channels in DSM cells. According to the postulated mechanism, the TRPM4 channels via sarcoplasmic reticulum Ca²⁺-dependent activation participate in a positive feedback loop to maximize DSM contractility by providing Na⁺-depolarizing conductance.

Figure 2

Simulated steady-state activation curve showing log (Cai). The solid line represents the result from simulation, where the solid filled triangle shows the adapted experimental data from Demion et al., 2007 [89].

Figure 3

DSM model showing initial fluctuation (a) and constant resting membrane potential maintained at −52 mV (b).

Figure 4

(a) The model generated AP (solid red line) and depolarization (dashed red line) with the current stimulus. (b) The model generated AP (solid red line), experimental AP (solid blue line), and simulated depolarization (dashed red line) with synaptic input stimulus.

Figure 5

DSM action potential after a 10% (solid red line) and 20% (solid black line) increase in the maximum conductance of the TRPM4 ion channel.

Figure 6

Sensitivity analysis of the TRPM4 channel conductance for DSM resting membrane potential and action potential duration.

Figure 7

DSM cell generates action potential (solid red line) with mutation of T-type Ca²⁺ channel. The dashed line depicts the absence of action potential.

Figure 8

Schematic overview of parallel conductance model for ionic current. Further elucidation is provided in the subsequent paragraph.

Figure 9

Schematic diagram of 10-state Markov model for BK channel. A detailed explanation is provided in the text.

Figure 10

Schematic diagram illustrating all ionic components within a DSM cell. The accompanying paragraph provides descriptions for each component.