L-type Ca channels (Ca 1.2/1.3) convey influx of calcium ions (Ca ) that orchestrate a bevy of biological responses including muscle contraction and gene transcription. Deficits in Ca 1 function play a vital role in cardiac and neurodevelopmental disorders. Yet conventional pharmacological approaches to upregulate Ca 1 are limited, as excessive Ca influx leads to cytotoxicity. Here, we develop a genetically encoded enhancer of Ca 1.2/1.3 channels (GeeC) to manipulate Ca entry in distinct physiological settings. Specifically, we functionalized a nanobody that targets the Ca macromolecular complex by attaching a minimal effector domain from a Ca 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 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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542531PMC
http://dx.doi.org/10.1101/2023.09.22.558856DOI Listing

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