The CAGE Framework (Calcium-Gated Excitability): From Single Neurotransmitters to Calcium States in the Tumor Microenvironment.

The tumor microenvironment (TME) is an innervated and neurochemically active setting. To date, its cholinergic and GABAergic signaling have largely been analyzed as separate systems, contributing to inconsistent findings across the literature. We propose a Calcium-Gated Excitability (CAGE) model, in which α7 nicotinic acetylcholine receptor (nAChR), α4β2 nAChR, GABA type A (GABAA) and type B (GABAB) receptors, and α2δ-1 converge on a single downstream variable: Ca2+ flux. α7 conducts Ca2+ directly; α4β2 may redirect cholinergic input toward GABA release; GABAA and GABAB set the direction of the calcium response through intracellular chloride-gradient state and opposing intracellular signaling branches; α2δ-1 sets the gain that determines whether depolarization reaches a functional threshold. The resulting calcium-axis configuration, defined by receptor functional state, chloride-gradient status, α2δ-1 gain, and ligand exposure, shapes Ca2+ output and constrains downstream biological responses. Under this framework, some divergent findings on acetylcholine, nicotine, and GABA become testable consequences of distinct calcium-regulatory configurations. CAGE yields testable predictions, including nonlinear nAChR dose-response curves, reversal of GABAA polarity, α2δ-1-dependent signal scaling, and spatially heterogeneous Ca2+ states. Studies evaluating nAChR- and GABA-receptor-targeted therapies without prior calcium-axis stratification may not be underpowered; they may be asking the wrong question.