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

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.