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

Mammalian voltage-gated calcium channels (Ca) play critical roles in cardiac excitability, synaptic transmission, and gene transcription. Dysfunctions in Ca are implicated in a variety of cardiac and neurodevelopmental disorders. Current pharmacological approaches to enhance Ca 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 Ca1.2, a key subtype of Ca, and boost Ca1-mediated Ca 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) waves enhance Ca conductance in Ca1.2 by resonating with the stretching mode of the -COO group in the selectivity filter. Electrophysiological recordings and Ca imaging confirm that these waves rapidly, reversibly, and non-thermally increase calcium influx of Ca1.2 in HEK293 cells and induce acute Ca signals in neurons. Furthermore, this irradiation upregulates critical Ca1 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 gating and Ca signaling and treating diseases characterized by deficits in Ca functions.