A Genetically Encoded Actuator Selectively Boosts L-type Calcium Channels in Diverse Physiological Settings

L-type Ca ²⁺ channels (Ca _V 1.2/1.3) convey influx of calcium ions (Ca ²⁺ ) that orchestrate a bevy of biological responses including muscle contraction and gene transcription. Deficits in Ca _V 1 function play a vital role in cardiac and neurodevelopmental disorders. Yet conventional pharmacological approaches to upregulate Ca _V 1 are limited, as excessive Ca ²⁺ influx leads to cytotoxicity. Here, we develop a genetically encoded enhancer of Ca _V 1.2/1.3 channels (GeeC) to manipulate Ca ²⁺ entry in distinct physiological settings. Specifically, we functionalized a nanobody that targets the Ca _V macromolecular complex by attaching a minimal effector domain from a Ca _V enhancer—leucine rich repeat containing protein 10 (Lrrc10). In cardiomyocytes, GeeC evoked a 3-fold increase in L-type current amplitude. In neurons, GeeC augmented excitation-transcription (E-T) coupling. In all, GeeC represents a powerful strategy to boost Ca _V 1.2/1.3 function in distinct physiological settings and, in so doing, lays the groundwork to illuminate new insights on neuronal and cardiac physiology and disease.