GABA and pancreatic beta-cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion.

Abstract

GABA, a major inhibitory neurotransmitter of the brain, is also present at high concentration in pancreatic islets. Current evidence suggests that within islets GABA is secreted from beta‐cells and regulates the function of mantle cells (alpha‐ and delta‐cells). In the nervous system GABA is stored in, and secreted from, synaptic vesicles. The mechanism of GABA secretion from beta‐cells remains to be elucidated. Recently the existence of synaptic‐like microvesicles has been demonstrated in some peptide‐secreting endocrine cells. The function of these vesicles is so far unknown. The proposed paracrine action of GABA in pancreatic islets makes beta‐cells a useful model system to explore the possibility that synaptic‐like microvesicles, like synaptic vesicles, are involved in the storage and release of non‐peptide neurotransmitters. We report here the presence of synaptic‐like microvesicles in beta‐cells and in beta‐cells. Some beta‐cells in culture were found to extend neurite‐like processes. When these were present, synaptic‐like microvesicles were particularly concentrated in their distal portions. The GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), was found to be localized around synaptic‐like microvesicles. This was similar to the localization of GAD around synaptic vesicles in GABA‐secreting neurons. GABA immunoreactivity was found to be concentrated in regions of beta‐cells which were enriched in synaptic‐like microvesicles. These findings suggest that in beta‐cells synaptic‐like microvesicles are storage organelles for GABA and support the hypothesis that storage of non‐peptide signal molecules destined for secretion might be a general feature of synaptic‐like microvesicles of endocrine cells.

Nutrient regulation of gamma-aminobutyric acid release from islet beta cells

“…They are consistent with previous findings that the secretory vesicles are not the main site for GABA storage in the beta cells [9]. Most cellular GABA is stored in microvesicles which resemble the SLMV in neurons [10]. By measuring the GABA accumulation in the Data represent means ± SEM of 4 independent experiments.…”

“…Addition of glutamine is expected to provide amino acids for protein synthesis and substrates for the glutamate dehydrogenase and decarboxylase reactions. GAD activity results in formation of GABA which can be transaminated in the mitochondria [9] or transported into synaptic-like microvesicles (SLMV) [10]. The release of GABA in the extracellular medium is thought to occur by exocytosis of the SLMV [10] but is also conceivable from the cytoplasm through GABA-transporters in the plasma membrane.…”

“…GAD activity results in formation of GABA which can be transaminated in the mitochondria [9] or transported into synaptic-like microvesicles (SLMV) [10]. The release of GABA in the extracellular medium is thought to occur by exocytosis of the SLMV [10] but is also conceivable from the cytoplasm through GABA-transporters in the plasma membrane. The latter mechanism may lead to a higher GABA content in the medium when GABA production is increased by glutamine and the excess of cytoplasmic GABA is not (completely) catalysed in the mitochondria or stored in the SLMV.…”

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

“…GAD is present not only in GABAnergic neurons, but also in pancreatic -cells, testis, liver, kidney, and adrenal glands (2,3).…”

The role of anti-glutamic acid decarboxylase autoantibodies in mood disorders

“…However, GAD and GABA were also detected in the pancreas where the latter is stored in synaptic-like vesicles in islet beta cells. [32][33][34] GAD exists in two isoforms: one of a molecular size of 65 kDa is termed GAD 65 , whilst the other, of 67 kDa, is termed GAD 67 . Each of them plays a distinct role: GAD 65 is the product of a gene located on chromosome 10 whereas GAD 67 gene is on chromosome 2.…”