UC San Diego

The insulin secreting pancreatic [beta] cells, by virtue of their pattern of protein expression and the architecture of their secretory apparatus, share many features with neurons in the central nervous system (CNS). The work described throughout this dissertation arose from the observation that the [beta] cells' expression of the machinery necessary for GABAergic neurotransmission makes the [beta]-cell cellular "phenotype" very much resemble that of an inhibitory synapse. This observation led to the overarching hypothesis that key insights into the functional maturation of [beta] cells could be derived from existing knowledge of the development, differentiation and maintenance of GABAergic synapses in the CNS. [beta] cells contain synaptic-like microvesicles of which the origin, trafficking and role are poorly understood. Here, I demonstrate that the biogenesis of these vesicles in [beta] cells is driven by adaptor proteins that are important for the formation of vesicular GABA transporter-containing synaptic vesicles in the CNS. Additionally, high level expression of the vesicular GABA transporter is detected in both human and rat [beta] cells, and a novel glucose-regulated variant of this protein is described. These findings suggest that [beta]-cells and neurons share molecules and mechanisms important for mediating the neuron-specific GABAergic membrane trafficking pathways that underlie synaptic vesicle formation. The synaptogenic adhesion molecules, neuroligin and neurexin, drive synapse formation in vitro and regulate the differentiation of nascent synapses into either glutamatergic or GABAergic fully mature nerve terminals. Here, the expression of those neuroligin and neurexin family members important for the maturation of GABAergic synapses, and the expression of their intracellular, GABAergic binding partners, is demonstrated in [beta]-cells. Neuroligin expression is revealed to be important for glucose-stimulated insulin secretion and evidence is presented that it may drive the proper assembly of the insulin secretory apparatus. Neuroligin is found to affect insulin secretion through a neurexin- independent mechanism in rat [beta]-cells. Overall, these results indicate that knowledge of the pathways that guide GABAergic synapse formation and function will aid in our understanding of [beta]-cell development and functional differentiation, and may yield important targets for remedying some of the [beta]-cell dysfunction that occurs during the pathogenesis of diabetes