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Background: The use of light to control the activity of living cells is a promising approach in cardiac research due to its unparalleled spatio-temporal selectivity and minimal invasiveness. Ziapin2, a newly synthesized azobenzene compound, has recently been reported as an efficient tool for light-driven modulation of excitation-contraction coupling (ECC) in human-induced pluripotent stem cells-derived cardiomyocytes. However, the exact biophysical mechanism of this process remains incompletely understood., Methods: To address this, we performed a detailed electrophysiological characterization in a more mature cardiac model, specifically adult mouse ventricular myocytes (AMVMs)., Results: Our in vitro results demonstrate that Ziapin2 can photomodulate cardiac ECC in mature AMVMs without affecting the main transporters and receptors located within the sarcolemma. We established a connection between Ziapin2-induced membrane thickness modulation and light-generated action potentials by showcasing the pivotal role of stretch-activated channels (SACs). Notably, our experimental findings, through pharmacological blockade, suggest that non-selective SACs might serve as the biological culprit responsible for the effect., Conclusions: Taken together, these findings elucidate the intricacies of Ziapin2-mediated photostimulation mechanism and open new perspectives for its application in cardiac research., Competing Interests: Declarations. Ethics approval and consent to participate: All experiments involving animals confirmed to the guidelines for Animal Care endorsed by the Milano-Bicocca and to the Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes. Consent for publication: Not applicable., (© 2024. The Author(s).)

Optical technologies allowing modulation of neuronal activity at high spatio-temporal resolution are becoming paramount in neuroscience. In this respect, azobenzene-based photoswitches are promising nanoscale tools for neuronal photostimulation. Here we engineered a light-sensitive azobenzene compound (Ziapin2) that stably partitions into the plasma membrane and causes its thinning through trans-dimerization in the dark, resulting in an increased membrane capacitance at steady state. We demonstrated that in neurons loaded with the compound, millisecond pulses of visible light induce a transient hyperpolarization followed by a delayed depolarization that triggers action potential firing. These effects are persistent and can be evoked in vivo up to 7 days, proving the potential of Ziapin2 for the modulation of membrane capacitance in the millisecond timescale, without directly affecting ion channels or local temperature.