GABA in the Endocrine Pancreas

-Aminobutyric acid (GABA) is a principal nonpeptidal neurotransmitter with a well-characterized role as an inhibitor of neuronal firing in the CNS (Cherubini et al., 1991; Thomas-Reetz and De Camilli, 1994). GABA is also found in other tissues, such as the endocrine pancreas (Thomas-Reetz and De Camilli, 1994). In the neuron, GABA is synthesized in close proximity to synaptic vesicles, it is produced from glutamate by the enzyme glutamate decarboxylase (GAD) and then transported into the synaptic vesicles against a proton electrochemical gradient (Thomas-Reetz and De Camilli, 1994). Exocytosis of neuronal synaptic vesicles is triggered when voltage-sensitive calcium channels open, causing a transient increase in cytosolic calcium. GABA is consequently released into the synaptic space, where it interacts with ionotropic receptors on the postsynaptic membrane, increasing their chloride conductance and thereby inducing membrane hyperpolarization and inhibition of exocytosis (Cherubini et al., 1991; Thomas-Reetz and De Camilli, 1994). However, when the electrochemical chloride gradient across the membrane is directed outward, as in neonatal hippocampal neurons, GABA is excitatory (Cherubini et al., 1991). The endocrine pancreas also contains high concentrations of GABA, and the 65-kD isoform of GAD (GAD 65) predominantly in the core of the islets of Langerhans, where insulin-producing -cells are located (Sorenson et al., 1991; Thomas-Reetz and De Camilli, 1994; Chessler et al., 2002). For more than three decades the role of -cell GABA has puzzled scientists, with interest intensifying on the discovery that GAD 65 is one of the major autoantigens in type 1 diabetes mellitus, a disease in which -cells are systematically destroyed by an autoimmune mechanism (Yoon et al., 1999). Evidence suggests that -cell GABA localizes to synaptic-like microvesicles (SLMVs) and is exocytosed in a regulated manner, as it is in neurons (ThomasReetz and De Camilli, 1994). What are the stimuli for -cell GABA release? Which islet cell type/s are the targets of this fast-acting signaling molecule and what, if any, are its effects on hormone secretion? These important questions have remained unanswered largely because of the difficulty in obtaining quantitative amounts of secreted GABA to detect temporal changes in GABA release. A fresh approach to the detection of secreted GABA, providing both high temporal resolution and sensitivity, is presented by Braun and colleagues in this issue (Braun et al., 2004). This new methodology and its application contribute a significant step toward the characterization of the mechanisms of -cell GABA release and offers a platform for further studies of GABA stimulus-secretion coupling and SLMV exocytosis.