Glycine, GABA and their transporters in pancreatic islets of Langerhans: evidence for a paracrine transmitter interplay

Abstract

To elucidate the possible roles of the CNS neurotransmitters glycine and GABA in neuroendocrine paracrine signalling, we investigated their localizations, and those of their transport proteins, by confocal immunofluorescence and quantitative post-embedding immuno-electron microscopy in the pancreatic islets of Langerhans. We show that A-cells contain glycine in synaptic-like microvesicles as well as in secretory granules. A-cells express the macromolecules necessary to: (1) concentrate glycine within both organelle types before release (the vesicular GABA/glycine transporter VGAT=VIAAT); and to (2) take up the transmitter from the extracellular space (the plasma membrane glycine transporter GLYT2). Also B-cells have glycine in their microvesicles and granules, but the microvesicle/cytosol ratio is lower than in A-cells, consistent with the presence of GABA (which competes with glycine for vesicular uptake) in the cytosol at a much higher concentration in B-cells than in A-cells. Both A- and B-cells contain GABA in their microvesicles and secretory granules, and the membranes of the two organelle types contain VGAT in both cell types. A-cells as well as B-cells express a plasma membrane transporter GAT3 that mediates uptake of GABA. The localization of VGAT in the cores of A-cell secretory granules, and in the secretory granule membranes in both cell types, indicates novel aspects of the mechanisms for release of glycine and GABA. The discovery that both A- and B-cells possess the molecular machinery for the evoked release of both glycine and GABA from synaptic-like microvesicles suggests that both of the principal inhibitory transmitters in the brain participate in paracrine signalling in the pancreas.

Plant synapses: actin-based domains for cell-to-cell communication

“…Moreover, the neuronal transmitters GABA and glycine, and their vesicular transporters, are essential for paracrine transmitter interplay in the pancreas [27]. All these findings strongly support the 'conscious cell' concept proposed by Lynn Margulis -that all eukaryotic cells are able to use neuronal principles for controlling their complex behavior in the face of the huge amount of information that cells continuously receive, store and process for making adaptive decisions about their further states and activities [28].…”

Identification and characterization of a novel isoform of the vesicular γ-aminobutyric acid transporter with glucose-regulated expression in rat islets

“…Unexpectedly, VIAAT was found to localize to the glucagon-containing secretory granules rather than to the synaptic-like microvesicles also present in islet cells. In contrast, Gammelsaeter et al (2004) identified VIAAT in both secretory granules and microvesicles in rat islet cells and also detected comparatively low levels in the cells.…”

“…In the islets, it probably also functions as an intercellular signaling molecule, perhaps -as there is evidence to suggest -as a paracrine or autocrine regulator of insulin or glucagon secretion (Chessler & Lernmark 2000, Braun et al 2004a. Recent evidence suggests that a second inhibitory neurotransmitter, glycine, also plays a role in islet function (Gammelsaeter et al 2004).…”

A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes

“…Immunohistochemistry and immunogold electron microscopy show that rat b-cells express the vesicular amino acid transporter (VIAAT/VGAT), which mediates glycine uptake into synaptic vesicles in neurons and accumulates glycine in secretory granules (30). These findings, and the ability of strychnine to inhibit insulin secretion from human islets (above), suggest that b-cells may release glycine by exocytosis to mediate autocrine signaling.…”