Molecular mechanism of L-glutamate and GABA-mediated regulation of secretion of glucagon and insulin in islets of Langerhans

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Vesicular glutamate transporter (VGLUT) and vesicular GABA transporter (VGAT) play essential roles in the glutamatergic and GABAergic chemical transduction, respectively. VGLUT and VGAT are present not only in the neuronal synaptic vesicles but also in the glucagon-containing secretory granules of A cells of islets of Langerhans, and are responsible for vesicular storage of glutamate and GABA, respectively. This research aimed to reveal the molecular mechanism of the glutamate- and GABA-mediated regulation of secretion of glucagon and insulin in the islets. During three years, we have obtained the following important results.(1)We have revealed topology of VGLUT2.(2)We have established an in vitro assay system for VGLUT, and identified some essential amino acid residues for transport of glutamate as well as targeting.(3)We have established an in vitro assay system for VGAT.(4)We have observed decreased glutamatergic signaling in VGLUT1 KO mice.(5)We have identified and characterized glutamate signaling pathway in intestinal L cells.(6)We have identified and characterized a series of receptors for regulation of secretion of insulin and glucagon.