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

OBJECTIVE: Paracrine signaling via gamma-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 alpha(1)beta(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 alpha(2), beta(3,) gamma(2), and pi subunits in human islets. Patch-clamp experiments revealed expression of GABA(A)R Cl(-) channels in 52% of beta-cells (current density 9 pA/pF), 91% of delta-cells (current density 148 pA/pF), and 6% of alpha-cells (current density 2 pA/pF). Expression of GABA(A)R subunits in islet cells was confirmed by immunohistochemistry. beta-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 beta-cells and stimulated action potential firing in beta-cells exposed to glucose. CONCLUSIONS: Signaling via GABA and GABA(A)R constitutes an autocrine positive feedback loop in human beta-cells. The presence of GABA(A)R in non-beta-cells suggests that GABA may also be involved in the regulation of somatostatin and glucagon secretion

Mice Deficient in GEM GTPase Show Abnormal Glucose Homeostasis Due to Defects in Beta-Cell Calcium Handling

Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo

Nature Neuroscience

Through the development of novel PKC biosensors, the authors describe how PKCα, but not other classical isozymes, facilitates plasticity in dendritic regions through the integration of recent synaptic plasticity with current, local synaptic input