Quantitative Study of pharmacological regulation of TRPM channel in Urinary Bladder over Activity
Authors: Mahapatra Chitaranjan , Manchanda Rohit 
Published: June 2021

Enhanced spontaneous contraction of the detrusor smooth muscle (DSM) is associated with overactive bladder (OAB), a pathophysiological syndrome that affects millions of individuals socially. The anticholinergic drug “Oxybutynin”, a potent drug used for overactive bladder, causes several side effects such as dry mouth, complications in visual functions, constipation, and somnolence. Therefore, the current research is focused to identify alternative pathways with the potential to reduce DSM contractility for the treatment of OAB. The hyperexcitability due to the interplay of various active ion channel evokes spontaneous action potentials (sAP), which is essential for generating spontaneous contraction. Recently, transient receptor potential melastatin‐4 (TRPM4) channels have been identified in the guinea pig, rodents, and human. The aim of this current study is to quantify the modulating effects of TRPM4 in regulating DSM cell excitability.

The computational electrophysiological model provides a unique platform to describe the excitable cell AP generation in silico and gaining insight into the interplay between the ion channel contributions. We, therefore, developed the electrophysiological model of a single DSM cell to simulate the AP generation. The model was designed to be sufficiently detailed to include the main known aspects of mouse DSM cell behavior while retaining enough simplicity to enable its parameterization using biophysical data from various experiments.

The TRPM4 channel current (Itrp) is computed upon the steady‐state values of the activation and inactivation parameters. In this model, all ionic conductances were tuned to set the resting membrane potential (RMP) at − 50 mV. The maximum conductance value of the Itrp channel was set to 0.00001 mho/cm2. By setting the maximum conductance at a higher value (0.00005 mho/cm2), this DSM cell model generated AP with the higher RMP value. Again, after increasing the maximum conductance to 0.0001 mho/cm2, the simulated AP showed a more depolarized RMP value. This simulation showed that the activation of more TRPM channels will cause overactive bladder by increasing the excitability of DSM cell. As the TRPM channels are calcium‐dependent, any spontaneous elevation of intracellular calcium concentration may cause bladder over activities by opening these TRPM channels.

Our approach provides a “virtual workbench” for simulating DSM cell AP with maximal objectivity and faithfulness with regard to recordings in experiments. We investigated the modulating aspect of the Itrp current in DSM cell excitability. As the Itrp channel blockers hyperpolarize the DSM membrane, the pharmacological maneuver of the TRPM4 channel blocker 9‐phenanthrol may play a novel approach to the treatment of bladder overactivity.

Support or Funding Information

This work is supported in part by Department of Biotechnology (DBT), India (grant number BT/PR12973/MED/122/47/2016).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.