Novel chemogenetic approaches in modulating calcium signaling

Calcium (Ca2+) signals regulate diverse processes ranging from neurotransmission and muscle contraction to gene expression, immune response, and cell death. Conventional pharmacological agents are readily applied but often lack molecular and cell-type specificity, whereas genetic perturbations offer greater precision but are typically slow and difficult to reverse. Chemogenetic systems bridge these approaches by combining genetically encoded protein actuators with exogenous chemical ligands. The present review summarizes emerging chemogenetic strategies that modulate Ca2+ signaling at distinct steps of the signaling cascade. These include engineered G protein-coupled receptors, chemically inducible receptor tyrosine kinases, direct actuators and inhibitors of STIM-ORAI coupling, genetically encoded blockers of voltage-gated Ca2+ channels, and engineered ligand-gated ion channels. We also discuss prospective designs targeting the phospholipase C signaling axis. Collectively, these approaches enable reversible and cell-specific modulation of Ca2+ dynamics.