BPS2026 – A novel mechanism for long distance calcium signaling without gap junctions

Long-range calcium (Ca 2+ ) signaling governs vital processes like airway contraction, insulin production, and regulation of blood pressure. Additionally, dysregulation of these signals can lead to diseases, such as cancer, Huntington’s disease, and hypertension. Traditionally, this long-range Ca 2+ signaling is attributed to diffusion of a signaling molecule, IP3, through gap junctions. However, recent studies have shown that IP3 diffuses 30 times slower than previously reported, making it significantly slower than Ca 2+ diffusion and is therefore insufficient for long-distance Ca 2+ propagation. In this study, we identify a novel mechanism in which intercellular forces, rather than molecular diffusion alone, drive long-distance intercellular calcium signaling. We show that human smooth muscle cells (SMCs) can detect and communicate the stiffness of the extracellular matrix (ECM) over distances eight times their length utilizing Ca 2+ signaling, far exceeding the range of traditional IP3-based chemical signaling mechanisms. Using an in vitro informed computational model, we demonstrate that intercellular forces trigger regenerative cytosolic Ca 2+ oscillations in neighboring SMCs. We also show that oscillation frequency increases in response to applied force from neighboring cells. Furthermore, this force-based communication synchronizes calcium dynamics between cells and therefore facilitates long range Ca 2+ communication. Specifically, this synchronization enables cells adhered to a stiff ECM (13 kPa) to amplify and coordinate Ca 2+ oscillation frequency and contractility in neighboring cells on an adjoining soft ECM (0.3 kPa). Our findings propose a new paradigm for calcium signaling, wherein mechanically induced IP3 release serves as a regenerative mechanism for long-range calcium propagation. These findings provide critical insights into how localized ECM remodeling produces systemic effects, offering a framework to understand early stages of disease progression in asthma, fibrosis, and cancer.