GABA Regulates Ca²⁺ Oscillations and Synchronization in Pancreatic Beta Cells

Background/Objectives: Gamma-aminobutyric acid (GABA) is increasingly recognized as an important modulator of pancreatic beta-cell function, but the mechanisms by which it regulates intracellular Ca²⁺ oscillations and coordinated beta-cell activity remain insufficiently understood. The aim of this study was to investigate how GABA influences the amplitude, frequency, phase adjustment, entrainment, and synchronization of beta-cell Ca²⁺ oscillations. Methods: We developed an extended mathematical model based on our previously established Dual Anaplerotic Model of the GABA shunt. The model incorporates explicit dynamics of cytosolic Ca²⁺, endoplasmic reticulum Ca²⁺, ATP, and a regulatory variable controlling Ca2+ influx, while extracellular GABA is represented as a delayed interstitial signal feeding back on cellular excitability. Single-cell and two-cell simulations were performed to analyze GABA-dependent oscillatory regulation and intercellular coupling. Results: The model reproduced key experimental observations under both control and GABA-deficient conditions, including reduced Ca²⁺-oscillation amplitude and prolonged oscillation period when GABA production was suppressed. Mechanistically, GABA affected single-cell oscillations through two complementary pathways: metabolically, by modulating ATP production through PEP-related and TCA-related contributions linked to the GABA shunt; and extracellularly, by adjusting the phase of Ca²⁺ influx through fast and delayed inhibitory feedback. In the two-cell model, delayed interstitial GABA signaling was sufficient to entrain and synchronize non-identical oscillators over finite ranges of parameter mismatch, and weak effective electrical coupling further broadened these synchronization ranges. Conclusions: GABA acts as a dual regulator of beta-cell dynamics, linking intracellular metabolism to Ca²⁺-oscillation patterning and promoting coordinated activity through intercellular phase adjustment. The model provides a mechanistic framework connecting GABA metabolism, ATP dynamics, Ca²⁺ signaling, and beta-cell synchronization in pancreatic islets.