Optical Control of Cardiac Function with a Photoswitchable Ligand

Remote control of physiological functions with light offers the promise of unveiling their complex spatiotemporal dynamics in vivo and enabling highly focalized therapeutic interventions with reduced systemic toxicity. Optogenetic methods have been implemented in the heart, but the need of genetic manipulation jeopardizes clinical applicability. In order to take full advantage of light manipulation in wildtype animals, we have developed a compound that can control cardiac function in a pharmacologically specific and light-regulated manner. The molecule, named PAI, was designed by introduction of a photoswitch into the molecular structure of an M2 mAChR agonist. PAI can be reversibly photoisomerized between cis and trans configurations under UVA and visible light, respectively. In vitro assays revealed that PAI enables light-dependent activation of M2 mAChRs. Furthermore, we showed that its photoisomers display different cardiac effects in rats, and demonstrated reversible, real-time photocontrol of cardiac function in wildtype tadpoles. Finally, we proved that PAI can also effectively activate M2 receptors using two-photon excitation with NIR light, which paves the way for further applications in more complex animal systems.