A genetically encoded actuator boosts L-type calcium channel function in diverse physiological settings | Science Advances

L-type Ca ²⁺ channels (Ca _V 1.2/1.3) convey influx of calcium ions that orchestrate a bevy of biological responses including muscle contraction, neuronal function, and gene transcription. Deficits in Ca _V 1 function play a vital role in cardiac and neurodevelopmental disorders. Here, we develop a genetically encoded enhancer of Ca _V 1.2/1.3 channels (GeeC _L ) to manipulate Ca ²⁺ entry in distinct physiological settings. We functionalized a nanobody that targets the Ca _V complex by attaching a minimal effector domain from an endogenous Ca _V modulator—leucine-rich repeat containing protein 10 (Lrrc10). In cardiomyocytes, GeeC _L selectively increased L-type current amplitude. In neurons in vitro and in vivo, GeeC _L augmented excitation-transcription (E-T) coupling. In all, GeeC _L represents a powerful strategy to boost Ca _V 1.2/1.3 function and lays the groundwork to illuminate insights on neuronal and cardiac physiology and disease.