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Optogenetic defibrillation has emerged as a promising anti\u2010arrhythmic strategy based on photoactivation of channelrhodopsins, yet the efficacy and potential adverse consequences of activating different classes of light\u2010gated ion channels have not been systematically evaluated. Previous studies assessed either cation (e.g. ChR2) or anion (e.g. GtACR1) non\u2010selective channels, both of which depolarize resting cardiomyocytes. Recently identified light\u2010gated K\n +<\/jats:sup>\n channels (e.g. WiChR) suppress cardiomyocyte activity while maintaining the membrane potential near its resting state, but their defibrillation potential remains unexplored. We used computational simulations to compare ChR2, GtACR1 and WiChR. Single\u2010cell simulations showed that ChR2 and GtACR1 markedly increased diastolic intracellular Ca\n 2+<\/jats:sup>\n (by 42.6% and 52.6%, respectively), whereas WiChR induced only minimal changes (by 4.0%), suggesting lower pro\u2010arrhythmogenic risk. WiChR, however, slightly increased intracellular Na\n +<\/jats:sup>\n (by 15.1%\n vs<\/jats:italic>\n . 0.1% and 3.4% for ChR2 and GtACR1), consistent with the residual Na\n +<\/jats:sup>\n permeability of currently available K\n +<\/jats:sup>\n \u2010conducting channelrhodopsins. Simulations in human ventricles and atria showed that GtACR1 most effectively terminated re\u2010entrant arrhythmias at low light intensities, whereas WiChR achieved comparable efficacy at \u22655\u00a0mW\/mm\n 2<\/jats:sup>\n . Complementary tissue\u2010scale simulations revealed that defibrillation occurs through depolarization within the excitable gap followed by fast Na\n +<\/jats:sup>\n channel inactivation (ChR2 and partly GtACR1), or through reduced membrane resistance at sufficiently high light intensities (large\u2010conductance channels GtACR1 and WiChR). Overall, we demonstrate that channelrhodopsin ion selectivity is a key determinant of both optogenetic defibrillation efficacy and its underlying mechanisms.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Translational perspective<\/jats:title>\n \n Re\u2010entrant arrhythmias are a leading cause of sudden cardiac death. Standard therapies, including the activation of implantable cardioverter\u2010defibrillators, carry burdens such as pain and myocardial injury. Optogenetic defibrillation has been suggested as a potentially gentler alternative, replacing high\u2010voltage electrical shocks by photoactivation of light\u2010gated ion channels expressed in cardiac cells. Determining which light\u2010gated ion channel optimally balances efficacy and adverse effects on cardiac electrophysiology is critical for clinical translation. We addressed this question using computational simulations and validation experiments in zebrafish hearts. We identify ion selectivity as a key determinant of both the success rate for arrhythmia termination and the underlying mechanisms: non\u2010selective cation\u2010 and anion\u2010conducting channels terminate re\u2010entry efficiently while promoting intracellular Ca\n 2+<\/jats:sup>\n accumulation, a plausible substrate for pro\u2010arrhythmic side effects that could undermine therapeutic safety. K\n +<\/jats:sup>\n \u2010conducting channels largely avoid this pro\u2010arrhythmic risk by holding cardiomyocytes near their resting potential, albeit at the cost of requiring transmural illumination, while also causing mild Na\n +<\/jats:sup>\n accumulation attributable to residual Na\n +<\/jats:sup>\n permeability. Together, these trade\u2010offs define clear clinical implications: K\n +<\/jats:sup>\n \u2010conducting channels may provide the safest option for optogenetic defibrillation, particularly once variants with further enhanced K\n +<\/jats:sup>\n selectivity and red\u2010shifted activation spectra for improved operation within blood\u2010perfused myocardium become available.\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n We use computational simulations to compare cation non\u2010selective (ChR2), anion non\u2010selective (GtACR1) and K\n +<\/jats:sup>\n \u2010selective (WiChR) channelrhodopsins for optogenetic termination of re\u2010entrant arrhythmia.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Single\u2010cardiomyocyte simulations suggest that ChR2 and GtACR1 activation can cause progressive accumulation of intracellular Ca\n 2+<\/jats:sup>\n , which is minimized when using WiChR.\n <\/jats:p>\n <\/jats:list-item>\n \n Intracellular microelectrode recordings from hearts of transgenic adult zebrafish validate the simulated voltage dynamics seen with ChR2, GtACR1 or WiChR activation.<\/jats:p>\n <\/jats:list-item>\n \n Simulations of human left ventricles and atria indicate that GtACR1 is most effective in terminating re\u2010entrant arrhythmia at low light intensities, whereas WiChR becomes similarly effective at higher intensities.<\/jats:p>\n <\/jats:list-item>\n \n \n Tissue\u2010scale simulations indicate distinct defibrillation mechanisms: excitable gap extinction by\n de novo<\/jats:italic>\n action potential initiation followed by inactivation of fast Na\n +<\/jats:sup>\n channels for depolarizing channelrhodopsins (ChR2, GtACR1), and reduction in membrane resistance for the large\u2010conductance channels (GtACR1, WiChR), effectively clamping the membrane potential at each channel's reversal potential at high light levels.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp291707","type":"journal-article","created":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T06:31:20Z","timestamp":1792305080000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Channelrhodopsin ion selectivity determines mechanisms and efficacy of optogenetic defibrillation in human atria and ventricles"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1979-4122","authenticated-orcid":false,"given":"Sophia","family":"Ohnemus","sequence":"first","affiliation":[{"name":"Institute for Experimental Cardiovascular Medicine University Heart Center Freiburg \u2012 Bad Krozingen, Medical Faculty and Medical Center \u2013 University of Freiburg Freiburg im Breisgau Germany"},{"name":"Faculty of Mathematics and Physics University of Freiburg Freiburg im Breisgau Germany"},{"name":"Spemann Graduate School of Biology and Medicine (SGBM) University of Freiburg Freiburg 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