A molecular systems perspective on calcium oscillations beyond ion fluxes

Calcium (Ca²⁺) oscillations, marked by periodic fluctuations in cytosolic Ca²⁺ levels, are a universal feature of both excitable and non-excitable cells, regulating key functions like immune responses, neuronal activity and oocyte activation. Despite significant progress over the past few decades in identifying the molecular toolkits involved in Ca²⁺ mobilization, fundamental questions remain unresolved: How do Ca²⁺oscillations arise? In dynamical systems, oscillations arise as closed-loop trajectories in phase space, known as limit cycles. In this framework, [Ca²⁺] is the variable that oscillates along the limit cycle. Is [Ca²⁺] also the control parameter that defines the system's stability? Understanding how oscillations arise and how instability is controlled are essential for determining what these oscillations encode. This review revisits classic categorizations of Ca²⁺ oscillation models, focusing on the minimal mathematical models, their assumptions and gaps linking models with experimental data. We examine historical arguments in light of recent discoveries of plasma membrane lipid oscillations in non-excitable cells. While growing evidence support the pivotal role of lipid signaling in regulating Ca²⁺ dynamics, they mostly focused on the upstream role of signaling in Ca²⁺ mobilization, rather than viewing membrane-dependent signal transduction as the core control loop that is responsible for oscillatory Ca²⁺ dynamics. Here we summarize recent molecular studies of phosphoinositide signaling in modulating Ca²⁺ dynamics, by considering a broader chemical perspective as essential for understanding Ca²⁺ oscillations beyond ion fluxes.