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5.4 CONCLUSION
In this chapter, the current understanding of the molecular machinery
and mechanism of cell secretion and SNARE-induced membrane fusion
is presented. Porosomes are specialized plasma membrane structures
universally present in secretory cells, from exocrine and endocrine cells
to neuroendocrine cells and neurons. Since porosomes in exocrine and
neuroendocrine cells measure 100-180 nm, and only a 20-35% increase
in porosome diameter is demonstrated following the docking and fusion
of 0.2-1.2 μm in diameter secretory vesicles, it is concluded that secretory
vesicles “transiently” dock and fuse at the base of the porosome complex
to release their contents to the outside. Furthermore, isolated live cells in
a near-physiological buffer when imaged using AFM demonstrate the size
and shape of the secretory vesicles lying immediately below the apical
plasma membrane of the cell. Following exposure to a secretory stimulus,
secretory vesicles swell, followed by a decrease in vesicle size. No loss
of secretory vesicles is observed following secretion, demonstrating
transient fusion and partial discharge of vesicular contents during cell
secretion. In agreement, “secretory granules are recaptured largely intact
after stimulated exocytosis in cultured endocrine cells”,
“single synaptic
vesicles fusing transiently and successively without loss of identity”,
37
“zymogen granule exocytosis is characterized by long fusion pore
openings and preservation of vesicle lipid identity”.
38
This is in contrast to
the general belief that in mammalian cells, secretory vesicles completely
merge at the cell plasma membrane, resulting in passive diffusion of
vesicular contents to the cell exterior and the consequent retrieval of
excess membrane by endocytosis at a later time. Additionally, a major
logistical problem with complete merger of secretory vesicle membrane
at the cell plasma membrane is the generation of partially empty vesicles
following cell secretion observed in electron micrographs. It is fascinating
how even single-cell organisms have developed such specialized secretory
machinery, like the secretion apparatus of
36
, the
contractile vacuole in paramecium and the secretory structures in bacteria.
Hence, it comes as no surprise that mammalian cells have evolved such
highly specialized and sophisticated structure—the “porosome complex”
for the precise and regulated release of secretory products during cell
secretion. The discovery of the porosome, and an understanding of its
structure and dynamics at nanometre resolution and in real time in live
cells, its composition and its functional reconstitution in lipid membrane,
and the molecular mechanism of SNARE-induced membrane fusion have
greatly advanced our understanding of cell secretion. It is evident that
the secretory process in cells is a well-coordinated, highly regulated and
a finely tuned biomolecular orchestra. Clearly, these findings could not
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