Multiple kinetic components and the Ca2+ requirements of exocytosis

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Abstract
The use of caged–Ca 2+ compounds to stimulate Ca 2+ –dependent exocytosis has substantially increased our understanding of this complex process. By this approach, the existence of multiple kinetic components of exocytosis has been established. These components may correspond to a series of sequential steps that lead to a single fusion–ready state (sequential mechanism) or, alternatively, to heterogeneity in secretory vesicles or in fusion–ready states (parallel mechanism). It is suggested that both of these mechanisms can underlie exocytosis of a single type of vesicle (mixed sequential–parallel mechanism). Studies with caged–Ca 2+ compounds have also indicated that the Ca 2+ requirement for exocytosis is substantially greater than that suggested by conventional methodologies. This discrepancy is mainly attributable to the underestimation, by imaging studies with high–affinity Ca 2+ indicators (due to dye saturation), of the local increases in cytosolic Ca 2+ concentration that trigger the exocytosis of individual vesicles. The effects of local saturation of such indicators are explored by means of a simple theory.