γ-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic β-Cells

OBJECTIVE: Paracrine signaling via γ-aminobutyric acid (GABA) and GABA(A) receptors (GABA(A)Rs) has been documented in rodent islets. Here we have studied the importance of GABAergic signaling in human pancreatic islets. RESEARCH DESIGN AND METHODS: Expression of GABA(A)Rs in islet cells was investigated by quantitative PCR, immunohistochemistry, and patch-clamp experiments. Hormone release was measured from intact islets. GABA release was monitored by whole-cell patch-clamp measurements after adenoviral expression of α(1)β(1) GABA(A)R subunits. The subcellular localization of GABA was explored by electron microscopy. The effects of GABA on electrical activity were determined by perforated patch whole-cell recordings. RESULTS: PCR analysis detected relatively high levels of the mRNAs encoding GABA(A)R α(2), β(3,) γ(2), and π subunits in human islets. Patch-clamp experiments revealed expression of GABA(A)R Cl(−) channels in 52% of β-cells (current density 9 pA/pF), 91% of δ-cells (current density 148 pA/pF), and 6% of α-cells (current density 2 pA/pF). Expression of GABA(A)R subunits in islet cells was confirmed by immunohistochemistry. β-Cells secreted GABA both by glucose-dependent exocytosis of insulin-containing granules and by a glucose-independent mechanism. The GABA(A)R antagonist SR95531 inhibited insulin secretion elicited by 6 mmol/l glucose. Application of GABA depolarized β-cells and stimulated action potential firing in β-cells exposed to glucose. CONCLUSIONS: Signaling via GABA and GABA(A)R constitutes an autocrine positive feedback loop in human β-cells. The presence of GABA(A)R in non–β-cells suggests that GABA may also be involved in the regulation of somatostatin and glucagon secretion.