A Perspective on the Control of Mammalian Fertilization by Egg-Activated Ion Channels in Sperm: A Tale of Two Channels1

Abstract

Mammalian sperm contain a single large secretory vesicle, or acrosome. Exocytosis of this vesicle (the acrosome reaction) occurs as an early step in the gamete interaction process and is an essential prerequisite for late events, including sperm-egg fusion [1]. The control of fertilization is, from this perspective, a question of the regulation of a secretory event. It may be useful to compare sperm to other secretory systems. Typical somatic secretory cells such as mast cells, the neuronal presynaptic terminal, and exocrine cells contain large numbers of secretory vesicles whereas sperm possess a single acrosome. Those familiar somatic secretory models tolerate a low level of basal vesicle release that is augmented upon the arrival of an external stimulus. For example, miniature synaptic potentials are due to the stochastic release of individual vesicles, and stimuli, in the form of membrane depolarization, increase the number of released vesicles [2, 3]. In contrast, it can be argued that spontaneous exocytosis must be strictly controlled in sperm and may require a specialized regulatory mechanism. Key elements in this argument include the observations that 1) sperm that complete the acrosome reaction at a distance from eggs have decreased capacity to penetrate through the cumulus oophorus [4] and to adhere to the egg’s extracellular matrix, or zona pellucida [5, 6], and 2) sperm that fail to initiate acrosome reactions cannot penetrate the zona pellucida and hence are denied access to the egg plasma membrane [1]. Sperm consequently face an ‘‘acrosome reaction problem,’’ in which secretion must be coordinated with egg contact and yet spontaneous secretory rates must be suppressed. It is now understood that the initiation of acrosome reactions during egg contact is accomplished by the presence in the zona pellucida of an acrosome reaction-inducing agonist, the glycoprotein ZP3 [7]. However, individual sperm must still prevent spontaneous secretion until the time of sperm-egg contact. One common theme in the regulation of exocytotic processes is the general role of intracellular Ca21 ([Ca]i) as a mediator of stimulus-secretion coupling. In both sperm and somatic cells, elevations of [Ca]i are necessary and