Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist

Area of Science:

• Biomedical Engineering
• Cardiovascular Pharmacology
• Optogenetics

Background:

• Optogenetics offers precise control of physiological functions but clinical application is limited by genetic transfection requirements.
• Developing non-genetic methods for light-triggered modulation of cardiac function is crucial for therapeutic advancement.

Purpose of the Study:

• To present a novel photoswitchable compound (PAI) for light-dependent modulation of cardiac function without genetic manipulation.
• To demonstrate the efficacy of PAI in activating M2 muscarinic acetylcholine receptors (M2 mAChRs) and controlling cardiac activity.

Main Methods:

• Design of PAI by incorporating a photoswitch into an M2 mAChR agonist structure.
• In vitro assays to confirm light-dependent M2 mAChR activation by PAI.
• In vivo validation in mammalian models and translucent tadpoles to demonstrate photocontrol of cardiac function.

Main Results:

• PAI photoisomers exhibited distinct cardiac effects in a mammalian model.
• Reversible, real-time photocontrol of cardiac function was achieved in tadpoles.
• PAI effectively activated M2 receptors via two-photon excitation with near-infrared light, enabling deeper tissue penetration.

Conclusions:

• PAI provides a non-genetic, light-inducible method for modulating cardiac function.
• This approach overcomes limitations of traditional optogenetics, paving the way for new cardiac therapies.
• Near-infrared light activation expands possibilities for intravital cardiac imaging and control.