Bean A J, Seifert R, Chen Y A, Sacks R, Scheller R H
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine, California 94305, USA.
Nature. 1997 Feb 27;385(6619):826-9. doi: 10.1038/385826a0.
Associations between proteins present on neurotransmitter-containing vesicles and on the presynaptic membrane are thought to underlie docking and fusion of synaptic vesicles with the plasma membrane, which are obligate steps in regulated neurotransmission. SNAP-25 resides on the plasma membrane and interacts with syntaxin (a plasma membrane t-SNARE) and VAMP (a vesicle v-SNARE) to form a core protein complex thought to be an intermediate in a biochemical pathway that is essential for vesicular transport. We have now characterized a protein, Hrs-2, that interacts with SNAP-25. The binding of Hrs-2 to SNAP-25 is inhibited by calcium in the physiological concentration range that supports synaptic transmission. Furthermore, Hrs-2 binds and hydrolyses nucleoside triphosphates with kinetics that suggest that ATP is the physiological substrate for this enzyme. Hrs-2 is expressed throughout the brain and is present in nerve terminals. Moreover, recombinant Hrs-2 inhibits calcium-triggered 3H-noradrenaline release from permeabilized PC12 cells. Our results suggest a role for Hrs-2 in regulating secretory processes through calcium- and nucleotide-dependent modulation of vesicle-trafficking protein complexes.
人们认为，存在于含神经递质囊泡和突触前膜上的蛋白质之间的关联是突触囊泡与质膜对接和融合的基础，而这是调节性神经传递中必不可少的步骤。SNAP-25存在于质膜上，并与 syntaxin（一种质膜 t-SNARE）和 VAMP（一种囊泡 v-SNARE）相互作用，形成一种核心蛋白复合物，该复合物被认为是囊泡运输所必需的生化途径中的一个中间体。我们现在鉴定了一种与SNAP-25相互作用的蛋白质Hrs-2。在支持突触传递的生理浓度范围内，钙会抑制Hrs-2与SNAP-25的结合。此外，Hrs-2结合并水解核苷三磷酸，其动力学表明ATP是该酶的生理底物。Hrs-2在整个大脑中表达，并存在于神经末梢。此外，重组Hrs-2可抑制钙触发的3H-去甲肾上腺素从通透的PC12细胞中释放。我们的结果表明，Hrs-2通过对囊泡运输蛋白复合物的钙依赖性和核苷酸依赖性调节，在调节分泌过程中发挥作用。
