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