In islets of Langerhans, the neurotransmitter γ-aminobutyric acid (GABA) acts as a paracrine and autocrine signal that regulates hormone release; however, the mechanisms by which β-cells secrete GABA are unclear. A study by Steinunn Baekkeskov, Alejandro Caicedo, Edward Phelps and colleagues highlights a new mechanism for pulsatile GABA secretion from cytosolic pools in β-cells.

A super-resolution image of a human β-cell obtained by stimulated emission depletion microscopy with α-tubulin coloured green and insulin coloured magenta. Image courtesy of Edward A. Phelps, École Polytechnique Fédérale de Lausanne, Switzerland, and University of Florida, USA.

In neurons, GABA is released via a secretory vesicular pathway; however, β-cells lack a vesicular GABA transporter. “Using up-to-date microscopy techniques, we surprisingly observed that GABA in human and rodent β-cells is almost entirely cytosolic,” says Baekkeskov, “which was an unexpected result that was difficult to synthesize with a neuron-like mode of vesicular GABA release.” Interestingly, cytosolic pools of GABA were depleted in pancreatic islets obtained from cadaveric human donors with either type 1 or type 2 diabetes mellitus, compared with islets from non-diabetic donors.

“A major challenge was to determine GABA release from human islets in real time,” explains Caicedo. “To this end, we used a method based on sniffer cells, which express receptors for GABA that, when activated, increase Ca2+ levels inside the cell.” Using the sniffer cells, the team were able to show that GABA is secreted from islets in a pulsatile fashion. Moreover, secretion depended on GABA content; that is, decreasing GABA levels decreased secretion and vice versa.

Analysis of available RNA sequencing datasets of human islets to identify GABA transporters, followed by functional studies, identified two proteins that transport cytosolic GABA across the plasma membrane in β-cells: VRAC, which facilitates efflux, and TauT, which mediates uptake.

Diabetes mellitus was associated with disrupted cytosolic GABA secretion

Next, using multiple complementary methods, the researchers showed that secretion of endogenous GABA from the cytosolic β-cell pool decreased insulin release and also stabilized the periodicity of glucose-responsive insulin secretion. Finally, GABA secretion in human islets from donors with type 1 or type 2 diabetes mellitus was examined. Diabetes mellitus was associated with disrupted cytosolic GABA secretion, hinting at a new potential mechanism of diabetes mellitus development.

“Our paper reveals a novel mechanism for GABA release from β-cells, namely VRAC-mediated GABA release,” concludes Phelps. “This research poses important new questions, including whether there is still a role for secretory vesicle release of GABA in β-cells and what the mechanism is that drives the pulsatile nature of cytosolic GABA being released from the β-cells.”