[Frontiers in Bioscience 6, d792-806, July 1, 2001]
CALCIUM AND THE CONTROL OF MAMMALIAN CORTICAL GRANULE EXOCYTOSIS
Allison L. Abbott1 and Tom Ducibella2
1
FIGURES
Figure 1. Diagram of the central role for the elevation of intracellular Ca2+ in stimulating the major events of mammalian egg activation. Note that both Ca2+ release and response mechanisms are required for these events. As discussed in the text, critical components of these two mechanisms develop just prior to ovulation and during meiotic maturation. CG cortical granule; ZP, zona pellucida.
Figure 2. Working model of fertilization-induced signal transduction pathways required for CG secretion and cell cycle progression. While several steps are shown within the box for CG release, steps for cell cycle progression are not shown since they are not the subject of this review. The three Ca2+ peaks represent oscillations upon fertilization which normally continue in much greater number for several hours. The question mark indicates evidence for a pathway based on in vitro data in other vertebrate eggs or parthenogenetic activation without sperm as well as unknown factors which induce CG exocytosis in response to Ca2+ elevation and/or kinase activation. PIP2, phosphoinositol bisphosphate; DAG, diacylglycerol; PKC, protein kinase C; IP3, inositol trisphosphate; ER, endoplasmic reticululum; MPF, maturation-promoting factor; CG, cortical granule.
Figure 3. Simple model of the catalytic cycle of CaMKII. Relevant to egg activation is the so-called "memory" phase of the cycle in which the enzyme can maintain activity (via autophosphorylation) even after intracellular Ca2+ levels have decreased. This could allow prolonged CaMKII activity during the hours of Ca2+ oscillations without continuous elevated cytosolic Ca2+ that is generally toxic to all cells. CaM, calmodulin; CaMKII, calcium-calmodulin protein kinase II.
Figure 4. A model for vesicle translocation from a cortical location to the plasma membrane where docking and fusion occur. Egg CGs share a requirement with neurons for vesicle stabilization in the cell cortex and stimulation of translocation upon an increase in intracellular Ca2+. Evidence is discussed in the text in which the protein, synapsin, tethers the vesicle in the resting pool of vesicles, whereas active CaMKII phosphorylates synapsin resulting in the loss of tethering. The mechanism of final translocation is not well understood. SV, synaptic vesicle; MF, microfilaments; CaMKII, calcium-calmodulin protein kinase II.
Figure 5. CGs may utilize a secretory mechanism similar to that of synaptic vesicles since similar secretory machinery proteins have been identified in the egg cortex or associated with CGs. The figure is a diagrammatic representation of the process of synaptic vesicle docking and fusion. CGs in eggs share a requirement with neurons for vesicle stabilization in the cell cortex and stimulation of translocation upon an increase in intracellular Ca2+. In the neuron model, note that the stimulus for exocytosis is the influx of extracellular Ca2+ via a plasma membrane channel, resulting in Ca2+ binding to synaptotagmin. Rabphilin is also thought to bind Ca2+. Some of the prominent protein players of the SNARE hypothesis are included, but many are not illustrated (see reviews, 73, 110-112). The vesicle SNARE, synaptobrevin, associates with the target SNAREs, syntaxin and SNAP-25, to form a trimeric complex involved in membrane fusion and exocytosis of the vesicle contents. In mammalian eggs, the initial large increase in cytosolic Ca2+ is primarily from intracellular Ca2+ stores in the endoplasmic reticulum, while subsequent oscillations appear to require extracellular Ca2+. Stars indicate vesicle contents.