A genetically encoded actuator boosts L-type calcium channel function in diverse physiological settings.

L-type Ca channels (Ca1.2/1.3) convey influx of calcium ions that orchestrate a bevy of biological responses including muscle contraction, neuronal function, and gene transcription. Deficits in Ca1 function play a vital role in cardiac and neurodevelopmental disorders. Here, we develop a genetically encoded enhancer of Ca1.2/1.3 channels (GeeC) to manipulate Ca entry in distinct physiological settings. We functionalized a nanobody that targets the Ca complex by attaching a minimal effector domain from an endogenous Ca modulator-leucine-rich repeat containing protein 10 (Lrrc10). In cardiomyocytes, GeeC selectively increased L-type current amplitude. In neurons in vitro and in vivo, GeeC augmented excitation-transcription (E-T) coupling. In all, GeeC represents a powerful strategy to boost Ca1.2/1.3 function and lays the groundwork to illuminate insights on neuronal and cardiac physiology and disease.