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

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.