# Cardiac action potential generation mechanisms via an intramembrane photoswitch. A simulation study

## TL;DR

This study uses a computational model to explain how a light-sensitive compound called Ziapin2 can generate heart cell action potentials by affecting membrane tension and calcium channels.

## Contribution

The study introduces a computational model that clarifies the role of stretch-activated channels in light-induced action potential generation in cardiac cells.

## Key findings

- The model accurately reproduces membrane capacitance and potential changes caused by Ziapin2 photoisomerization.
- Calcium-selective stretch-activated channels are identified as pivotal in light-driven action potential generation.
- The model aligns with in vitro observations in adult mouse ventricular myocytes.

## Abstract

Optical stimulation is emerging as a promising alternative to conventional methods for both research and therapeutic purposes due to its advantages, such as reduced energy consumption, minimal invasiveness, and exceptional spatial and temporal precision. Recently, we introduced Ziapin2, a novel light-sensitive azobenzene compound, as a tool to modulate cardiac cell excitability and contractility. The molecule proved to be effective in precisely regulating the excitation-contraction coupling process in both hiPS-derived cardiomyocytes and adult mouse ventricular myocytes (AMVMs). Experimental evidence suggests that stretch-activated channels (SACs) contribute to light-driven action potential (AP) generation, but the exact way this takes place remains unknown due to system complexity and lack of specific SAC blockers. Here, we aim to clarify the role of SACs and photostimulation mechanism by exploiting a computational model of murine AP that incorporates: 1) the variation in membrane capacitance resulting from the trans-cis isomerization of the molecule in response to light stimulation and 2) SACs activated by membrane tension due to the thickness variation induced by Ziapin2. Our numerical model accurately reproduces cell capacitance and membrane potential alterations induced by Ziapin2 photoisomerization. In addition, it elucidates the behavior observed experimentally in vitro in AMVMs, highlighting the pivotal role of calcium (Ca2+)-selective SACs in AP generation. The proposed model is thus a valid tool for cell behavior prediction in future experiments.