Calcium regulation of secretion in neuroendocrine cells

神经内分泌细胞分泌的钙调节

• 批准号: 7991652
• 负责人: THOMAS F. J. MARTIN
• 金额: $ 3.79万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-03 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991652
• 关键词: Affect; Affinity; Amines; Binding; Binding Proteins; Biogenic Amine Neurotransmitters; Biogenic Amines; Calcium; Cell membrane; Complement; Dense Core Vesicle; Dependence; Diabetes Mellitus; Docking; Drug Delivery Systems; Endocrine system; Event; Exhibits; Exocytosis; Extracellular Space; Glutamates; Hippocampus (Brain); In Vitro; Liposomes; Location; Mediating; Membrane Fusion; Mental Depression; Molecular; Nervous system structure; Neuroendocrine Cell; Neuromodulator; Neurons; Neuropeptides; Neurosecretory Systems; PC12 Cells; Pathology; Pathway interactions; Peptide Signal Sequences; Phosphatidylinositol 4,5-Diphosphate; Phospholipids; Physiological; Play; Presynaptic Terminals; Process; Protein Secretion; Proteins; Rattus; Reaction; Regulation; Research Personnel; Role; SNAP receptor; Secretory Vesicles; Site; Small Interfering RNA; Speed; Synapses; Synaptic Transmission; Synaptic Vesicles; Therapeutic Intervention; Vesicle; Work; base; gamma-Aminobutyric Acid; in vivo; insight; neurotrophic factor; novel; postsynaptic; presynaptic; programs; protein function; protein transport; rabphilin; reconstitution; relating to nervous system; synaptotagmin; syntaxin; syntaxin 1; trafficking

DESCRIPTION (provided by applicant): Neuropeptides, biogenic amines, and neurotrophins affect synaptic transmission by regulating pre- and postsynaptic function. The regulated release of these neuromodulators is mediated by the Ca2+-dependent fusion of dense-core vesicles (DCVs) with the plasma membrane. Although regulated DCV exocytosis is similar to the Ca2+-dependent exocytosis of synaptic vesicles (SVs) that mediate synaptic transmitter release, these processes differ in speed, latency, Ca2+ regulation and location. A fuller understanding of molecular mechanisms underlying Ca2+-triggered DCV fusion will reveal similarities and differences in the two vesicle fusion pathways that could identify unique drug targets for the selective inhibition of modulator secretion without inhibiting synaptic transmission. The protein CAPS (Ca2+-dependent activator protein in secretion) appears to be required for DCV but not SV exocytosis. We will elucidate the molecular mechanism of CAPS function in regulated DCV fusion and determine the physiological role of this protein in the nervous system. CAPS is a PIP2-binding protein that exhibits high affinity interactions with syntaxin, a key component of the SNARE fusion machinery. These interactions may mediate the function of CAPS at a late pre-fusion step in DCV exocytosis. CAPS also binds rabphilin, which may in part mediate CAPS interactions with DCVs. Our specific aims will be: 1. To determine the functional significance of CAPS-syntaxin interactions for DCV exocytosis; 2. To determine if CAPS functions as a PIP2 effector in DCV exocytosis; 3. To determine the basis for the selective role of CAPS in DCV exocytosis and whether this is mediated through rabphilin interactions; and 4. To determine the general role of CAPS in neural trafficking pathways that mediate neuropeptide, biogenic amine and neurotrophin secretion. The results from this work will contribute to understanding neural trafficking pathways and to the molecular basis for secretory vesicle fusion with the plasma membrane.

描述（由申请人提供）：神经肽、生物胺和神经营养因子通过调节突触前和突触后功能影响突触传递。这些神经调节剂的调节释放是由Ca2+依赖的致密核囊泡（DCVs）与质膜融合介导的。虽然受调节的DCV胞吐与介导突触递质释放的突触囊泡（SVs）的Ca2+依赖性胞吐相似，但这些过程在速度、潜伏期、Ca2+调节和位置上有所不同。更全面地了解Ca2+触发的DCV融合的分子机制将揭示两种囊泡融合途径的异同，从而确定选择性抑制调节剂分泌而不抑制突触传递的独特药物靶点。蛋白质CAPS （Ca2+依赖性激活蛋白分泌）似乎是DCV而不是SV胞吐所必需的。我们将阐明CAPS在调节DCV融合中的分子机制，并确定该蛋白在神经系统中的生理作用。CAPS是一种pip2结合蛋白，与syntaxin （SNARE融合机制的关键组成部分）表现出高亲和力相互作用。这些相互作用可能介导CAPS在DCV胞吐过程中融合前后期的功能。CAPS也结合亲rabphilin，这可能部分介导CAPS与DCVs的相互作用。我们的具体目标是：1。探讨CAPS-syntaxin相互作用对DCV胞吐的功能意义；2. 确定CAPS在DCV胞吐过程中是否作为PIP2效应物起作用；3. 确定CAPS在DCV胞吐中选择性作用的基础，以及这是否通过亲rabphilin相互作用介导；和4。确定CAPS在介导神经肽、生物胺和神经营养因子分泌的神经转运通路中的一般作用。这项工作的结果将有助于理解神经运输途径和分泌囊泡与质膜融合的分子基础。