Detrusor overactivity is associated with abnormal electrical activity in detrusor smooth muscle (DSM) cells, driven by dysregulated ion channel function. Among these, the transient receptor potential melastatin-4 (TRPM4) channel plays a critical role as a calcium-activated non-selective cation channel that contributes to membrane depolarization and excitability regulation. Experimental studies have demonstrated that TRPM4 channels significantly influence DSM contractility and resting membrane potential, suggesting their importance in bladder pathophysiology [1,2]. We hypothesize that TRPM4-mediated conductance is a primary determinant of membrane depolarization and action potential modulation in detrusor smooth muscle (DSM) cells. Specifically, increasing TRPM4 conductance enhances cellular excitability by lowering the action potential threshold and prolonging depolarization.
Aims:
To develop an in silico electrophysiology model integrating TRPM4 channel kinetics into DSM action potential dynamics.
To quantitatively evaluate the effect of TRPM4 conductance on resting membrane potential, action potential threshold, amplitude, and duration.
To assess the compensatory role of TRPM4 under altered ionic conditions.

This study employed an in silico electrophysiology approach using a single‑compartment Hodgkin–Huxley‑type model of DSM cells. The model incorporated major ionic currents, including voltage‑gated Na⁺, K⁺, and Ca²⁺ currents, as well as the TRPM4 calcium‑activated non‑selective cation current. TRPM4 conductance (gTRPM4) was varied between 0–2.5 nS/pF, with the reversal potential set between −40 and 0 mV under physiological conditions, and the intracellular calcium baseline fixed at 0.1 mM. The simulation protocol involved stepwise variation of TRPM4 conductance and measurement of resting membrane potential, action potential threshold, peak amplitude, and action potential duration (APD₅₀). Model validation was performed against previously reported electrophysiological data, ensuring consistency with experimental findings.

The simulation results revealed a clear conductance‑dependent modulation of DSM cell excitability. As TRPM4 conductance (gTRPM4) increased from 0.0 to 2.0 nS/pF, the resting membrane potential progressively depolarized from −60 mV to −45 mV, while the action potential threshold decreased from −42 mV to −35 mV. This was accompanied by an increase in action potential amplitude from 78 mV to 105 mV and a prolongation of action potential duration (APD₅₀) from 45 ms to 72 ms. Under elevated calcium conditions, TRPM4‑mediated inward current rose to approximately 2.2 pA/pF, supporting sustained depolarization and repetitive firing activity. A detailed quantitative summary of these findings is presented in Table 1.

The findings demonstrate that TRPM4 channels function as a calcium-dependent depolarizing amplifier in DSM cells. Increased TRPM4 conductance shifts the membrane potential toward a more excitable state, reducing the threshold for action potential initiation. The prolongation of action potential duration further indicates sustained inward current, which may contribute to pathological repetitive firing and bladder overactivity. Additionally, the ability of TRPM4 to maintain excitability under altered ionic conditions suggests a compensatory and stabilizing role in DSM electrophysiology.

This in silico electrophysiology study quantitatively establishes TRPM4 conductance as a key regulator of detrusor smooth muscle excitability. By modulating resting membrane potential, action potential threshold, and spike dynamics, TRPM4 channels play a central role in the pathogenesis of detrusor overactivity. These findings highlight TRPM4 as a promising therapeutic target for precision modulation of bladder function.

Launay, P., Fleig, A., Perraud, A. L., Scharenberg, A. M., Penner, R., & Kinet, J. P. (2002). TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell, 109(3), 397-407.
Smith, A. C., Parajuli, S. P., Hristov, K. L., Cheng, Q., Soder, R. P., Afeli, S. A., ... & Petkov, G. V. (2013). TRPM4 channel: a new player in urinary bladder smooth muscle function in rats. American Journal of Physiology-Renal Physiology, 304(7), F918-F929.

Continence 19S (2026) 102703
DOI: 10.1016/j.cont.2026.102703