Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
Sci Adv. 2024 Nov;10(44):eadq3374. doi: 10.1126/sciadv.adq3374. Epub 2024 Oct 30.
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.
L 型钙通道（Ca1.2/1.3）介导钙离子内流，调节包括肌肉收缩、神经元功能和基因转录在内的多种生物学反应。Ca1 功能缺陷在心脏和神经发育障碍中起着至关重要的作用。在这里，我们开发了一种基因编码的 Ca1.2/1.3 通道增强子（GeeC），以在不同的生理环境中操纵 Ca 进入。我们通过附着来自内源性钙调节剂富含亮氨酸重复蛋白 10（Lrrc10）的最小效应结构域，使靶向 Ca 复合物的纳米抗体具有功能。在心肌细胞中，GeeC 选择性增加 L 型电流幅度。在体外和体内神经元中，GeeC 增强了兴奋-转录（E-T）偶联。总之，GeeC 代表了一种增强 Ca1.2/1.3 功能的强大策略，并为阐明神经元和心脏生理学和疾病的见解奠定了基础。
