A Non‐Invasive and DNA‐free Approach to Upregulate Mammalian Voltage‐Gated Calcium Channels and Neuronal Calcium Signaling via Terahertz Stimulation

Abstract Mammalian voltage‐gated calcium channels (Ca V ) play critical roles in cardiac excitability, synaptic transmission, and gene transcription. Dysfunctions in Ca V are implicated in a variety of cardiac and neurodevelopmental disorders. Current pharmacological approaches to enhance Ca V activity are limited by off‐target effects, drug metabolism issues, cytotoxicity, and imprecise modulation. Additionally, genetically‐encoded channel activators and optogenetic tools are restricted by gene delivery challenges and biosafety concerns. Here a novel terahertz (THz) wave‐based method to upregulate Ca V 1.2, a key subtype of Ca V , and boost Ca V 1‐mediated Ca 2+ signaling in neurons without introducing exogenous DNA is presented. Using molecular dynamics simulations, it is shown that 42.5 THz (7.05 µm, 1418 cm −1 ) waves enhance Ca 2+ conductance in Ca V 1.2 by resonating with the stretching mode of the ‐COO − group in the selectivity filter. Electrophysiological recordings and Ca 2+ imaging confirm that these waves rapidly, reversibly, and non‐thermally increase calcium influx of Ca V 1.2 in HEK293 cells and induce acute Ca 2+ signals in neurons. Furthermore, this irradiation upregulates critical Ca V 1 signals, including CREB phosphorylation and c‐Fos expression, in vitro and in vivo, without raising significant biosafety risks. This DNA‐free, non‐invasive approach offers a promising approach for modulating Ca V gating and Ca 2+ signaling and treating diseases characterized by deficits in Ca V functions.