東京大学坪井貴司研究室

RESEARCH

Research interests

  Exocytosis of neurotransmitters, hormones or gut hormones contributes to the pathology of a wide variety of chronic neurological, endocrine, and metabolic syndromes. Research in our lab is focussed on identifying the signalling pathways and molecules controlling secretion from neurons, glia, endocrine, enteroendocrine, and neuroendocrine cells, with a special interest in ATP-sensitive potassium (KATP), voltage-gated (CaV), ligand-gated (glutamate and P2X), and receptor-operated (TRP) channels, G protein-coupled receptors, vesicular transporters (glutamate and nucleotide), and SNARE regulatory proteins (Doc2, Rims, CAPSs etc).  Most of our work is performed at the level of isolated primary cells and clonal cells using high resolution techniques including live cell imaging of calcium, cAMP, ATP and total internal reflection fluorescence (TIRF) and Nipkow-disk type confocal microscopy with various fluorescence-based biosensors).

The exocytosis in health and disease

  Exocytosis is a process in which an intracellular vesicle moves to the plasma membrane and subsequent fusion of the vesicular membrane and the plasma membrane ensues. Many cellular processes involve exocytosis.
   We are currently interested in the hormone secretion from the gastrointestinal tract (gut hormones). Since gut hormones play important roles in the control of appetite and insulin secretion. Glucagon-like peptide-1 (GLP-1), which is one of gut hormones, have recently proved to be highly successful for treating type 2 diabetes. Thus, manipulating the release of endogenous GLP-1 and other gut peptides, this would be identify novel treatments for diabetes and obesity. Understanding the mechanisms that underlie secretion from gut endocrine cells is central to this approach, and forms the focus of our research. Recent highlights of our research include (1) the discovery of ATP-sensitive potassium channels on ghrelin-secreting gut X/A-like cells, activation of which contribute to the glucose-dependent ghrelin secretion (see, Oya et al, J. Endocrinol. 2015), and (2) the first demonstration of GPRC6A, G protein-coupled L-amino acids sensing receptor regulation of GLP-1 secretion in small intestinal enteroendocrine L-cells (see, Oya et al, J. Biol. Chem, 2013).
   We are also interested in cellular mechanisms involved in experience-induced neuronal plasticity underlying learning, fear and anxiety. We are particularly interested in the role that extracellular proteases, their receptors (PARs) and the extracellular matrix play in experience-induced plasticity in the limbic system. We use an interdisciplinary approach to better understand the role of the above molecules in the central nervous system physiology.

Development of genetically-encoded fluorescence protein probes

  We use protein engineering to invent new tools for imaging dynamic biochemical events in live cells and tissues. We distribute these tools to cell biologists and neuroscientists who apply them to address questions ranging from fundamental mechanisms in cell biology, to the underlying causes of mental illness, to the development of novel therapeutics. Recent highlight of our research include the development of cAMP-sensitive fluorescence protein probes (Flamindo), discovery of the extracellular calcium influx activates adenylate cyclase 1 and potantiates insulin secretion (see, Kitaguchi et al, Biochem. J, 2013).