Role and regulation of intracellular calcium in acrosomal exocytosis

Calcium influx is required for the mammalian sperm acrosome reaction, an exocytotic event occurring in the sperm head after binding to the egg. Prior to this binding, the spermatozoon undergo, in the female reproductive tract, a series of biochemical transformations, collectively called capacitation. The first event in capacitation is the elevation of intracellular calcium, bicarbonate and hydrogen peroxide, which collectively activate adenylyl cyclase to produce cyclic-AMP, which activates protein kinase A. During capacitation, there is an increase in the membrane-bound phospholipase C, and this binding is highly stimulated by adding epidermal growth factor to the cells. We suggest that zona-pellucida binds to at least two different receptors in the sperm head plasma membrane. One is a G_i-coupled receptor that can activate phospholipase Cβ₁ and might regulate adenylyl cyclase to further enhance cyclic-AMP levels. The cyclic AMP activates protein kinase A to open a calcium channel in the outer acrosomal membrane, resulting in a relatively small rise in cytosolic calcium. This rise in Ca²⁺ leads to activation of phospholipase Cγ, which is coupled to the second tyrosine kinase receptor. The products of phospholipase C activity, diacylglycerol and inositol-trisphosphate (IP₃), will lead to activation of protein kinase C (PKC) and IP₃-receptor. PKC will open a calcium channel in the plasma membrane and IP₃ will activate the calcium channel in the outer acrosomal membrane, leading to a higher increase in cytosolic calcium. In addition, the depletion of calcium in the acrosome will activate a store-operated Ca²⁺ channel, resulting in a very fast increase in cytosolic calcium (300-500 nM), leading to membrane fusion and completing the acrosome reaction.