Trends in Neurosciences
ReviewComparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function
Section snippets
Ca2+-dependent exocytosis of small and large vesicles
Neurons and endocrine cells possess two distinct types of secretory vesicles that undergo Ca2+-dependent exocytosis: large dense-core vesicles (LVs) and small clear-core vesicles (SVs)13, 14. These two types of vesicles differ both in their biogenesis and in their contents. The kinetic properties of Ca2+-dependent exocytosis in clonal PC12 cells, in which SVs containing ACh and LVs containing monoamines have been well characterized, has been investigated15. Measurements of membrane capacitance (
Ca2+-dependent exocytosis of lysosomes
Large stepwise increases have been detected frequently in capacitance in CHO cells9. These increases were predicted to correspond to the fusion of organelles with a diameter of between 0.5 μm and 2 μm and they were induced selectively by smaller increases in [Ca2+]i. It was shown subsequently that lysosomes could undergo Ca2+-dependent exocytosis in CHO cells and also in normal rat kidney (NRK) epithelial cells31. The size distribution of lysosomes in these cells32 and the Ca2+ dependence of
Sequential exocytotic mechanisms and diversity in fusion-ready states
The experimental results already presented in this review indicate that more than one type of secretory organelle often undergoes Ca2+-dependent exocytosis in an individual cell. Such parallel exocytotic events for heterogeneous vesicles result in multiple components of exocytosis. In addition, exocytosis of a single vesicle is thought to be mediated by a sequence of intermediate reactions. Such a sequential mechanism could also contribute to multiple exocytotic components6, 18, 29, 30.
Functional implications of the kinetic diversity in exocytosis
The physiological implications of the diversity in the kinetics of exocytosis will now be considered. Physiological exocytosis is triggered by transient increases in [Ca2+]i, known as Ca2+ spikes. Given certain assumptions (Box 1, Fig. IB), the probability of vesicle exocytosis occurring is equal to the product of the rate constant of exocytosis (1/τ) and the duration of the Ca2+ spike (Δt). Thus, the time constant of exocytosis (τ) and the duration of the Ca2+ spike are equally important in
Two possible steps that determine the time constant of exocytosis
It is commonly believed that, in presynaptic terminals, a population of synaptic vesicles is docked or attached to the plasma membrane and is, therefore, able to undergo very fast exocytosis (Fig. 4A). In this context, docking is thought to facilitate rapid fusion. This view, however, appears to be too simplistic. Large dense-core vesicles are also docked to the plasma membrane in chromaffin43 and PC12 cells44 (Fig. 4B) but most of these vesicles undergo relatively slow exocytosis (Fig. 1, Fig.
Concluding remarks
Studies with caged-Ca2+ compounds have revealed an unexpected diversity in the kinetics of Ca2+-dependent exocytosis. This diversity appears to result from differences in the contributions of the Ca2+ binding, vesicle translocation and fusion reactions. The secretory functions of different cell types appear to make use of this diversity. For example, the very fast secretion of neurotransmitters at synapses appears to depend on the rapidity of Ca2+ binding, vesicle translocation and fusion
Acknowledgements
The author thanks J. Meldolesi, G.J. Augustine and E. Neher for helpful discussions, and H. Takagi, Y. Ninomiya, K. Ito, N. Takahashi and T. Kishimoto for collaborations in many aspects of this work. This author's research was supported by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan, a grant from the Toyota Foundation, a research grant from the Human Frontier Science Program, Research for the Future of the Japan Society for the Promotion of Science and
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