GABA Regulates Ca²⁺ Oscillations and Synchronization in Pancreatic Beta Cells

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.

We developed a reduced ATP-Ca²⁺ oscillation model, based on established beta-cell oscillatory frameworks, and coupled it to the GABA-shunt subsystem derived from our previously established Dual Anaplerotic Model. The model incorporates explicit dynamics of cytosolic Ca²⁺, endoplasmic reticulum Ca²⁺, ATP, and a regulatory variable controlling Ca²⁺ influx, while the interstitial GABA signal is represented as a delayed feedback signal acting on cellular excitability. Single-cell and two-cell simulations were performed to analyze GABA-dependent oscillatory regulation and intercellular coupling.

The model reproduced key experimental observations under both control and GABA-deficient conditions, including reduced Ca²⁺-oscillation amplitude and a 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 as an interstitial/paracrine signal, by adjusting the phase of Ca²⁺ influx through fast and delayed inhibitory feedback. In the reduced two-cell model, delayed interstitial GABA signaling could phase-lock non-identical oscillators over finite ranges of parameter mismatch. When included as an additional weak effective term, electrical coupling broadened these ranges, consistent with a complementary interaction between GABA-mediated phase adjustment and established electrical coupling.

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.