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The Journal of Neuroscience, March 23, 2005, 25(12):3095-3106; doi:10.1523/JNEUROSCI.4694-04.2005

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Cellular/Molecular
Mechanisms of Transport and Exocytosis of Dense-Core Granules Containing Tissue Plasminogen Activator in Developing Hippocampal Neurons

Michael A. Silverman,¹ Scooter Johnson,² Dmitri Gurkins,² Meredith Farmer,² Janis E. Lochner,³ Patrizia Rosa,⁴ and Bethe A. Scalettar²

¹Department of Biological Sciences, California State Polytechnic University, Pomona, California 91768, Departments of ²Physics and ³Chemistry, Lewis and Clark College, Portland, Oregon 97219, and ⁴Department of Medical Pharmacology, Consiglio Nazionale delle Ricerche-Institute of Neuroscience, Center of Cellular and Molecular Pharmacology, 20129 Milan, Italy

Dense-core granules (DCGs) are organelles found in specialized secretory cells, including neuroendocrine cells and neurons. Neuronal DCGs facilitate many critical processes, including the transport and secretion of proteins involved in learning, and yet their transport and exocytosis are poorly understood. We have used wide-field and total internal reflection fluorescence microscopy, in conjunction with transport theory, to visualize the transport and exocytosis of DCGs containing a tissue plasminogen activator-green fluorescent protein hybrid in cell bodies, neurites, and growth cones of developing hippocampal neurons and to quantify the roles that diffusion, directed motion, and immobility play in these processes. Our results demonstrate that shorter-ranged transport of DCGs near sites of exocytosis in hippocampal neurons and neuroendocrine cells differs markedly. Specifically, the immobile fraction of DCGs within growth cones and near the plasma membrane of hippocampal neurons is small and relatively unaltered by actin disruption, unlike in neuroendocrine cells. Moreover, transport of DCGs in these domains of hippocampal neurons is unusually heterogeneous, being significantly rapid and directed as well as slow and diffusive. Our results also demonstrate that exocytosis is preceded by substantial movement and heterogeneous transport; this movement may facilitate delivery of DCG cargo in hippocampal neurons, given the relatively low abundance of neuronal DCGs. In addition, the extensive mobility of DCGs in hippocampal neurons argues strongly against the hypothesis that cortical actin is a major barrier to membrane-proximal DCGs in these cells. Instead, our results suggest that extended release of DCG cargo from hippocampal neurons arises from heterogeneity in DCG mobility.

Key words: regulated secretion; actin cortex; GFP; neuroendocrine; diffusion; imaging

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Received May 8, 2004; revised February 6, 2005; accepted February 7, 2005.

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