Communication between female tract and sperm

Abstract

Signaling through [Ca²⁺]_i is central to regulation of sperm activity and is likely to be the mechanism by which signal from the female tract regulate motility of sperm. In a recent paper1 we showed that exposure of sperm to nitric oxide mobilizes stored Ca²⁺ in human sperm, an effect that occurs through nitrosylation of protein thiols. Not only did we find that NO• production by cells of the human female tract would be sufficient to elicit this effect, but progesterone, which is also present in the female tract and is synthesized by the oocyte vestments, acted synergistically with NO• to mobilize Ca²⁺ and enhance flagellar beating. Here we argue that a Ca²⁺ store at the junction of the sperm head and flagellum is subject to regulation by both progesterone and NO• and that ryanodine receptors at the store may be the point at which coincidence detection and synergistic interaction occurs.

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Acknowledgements

This work was supported by The Wellcome Trust (078905). Machado-Oliveira G was in receipt of a scholarship from Fundação para a Ciência e Tecnologia (FCT) Portugal (SFRH/BD/17780/2004).

Figures and Tables

Figure 1 (A) Transport of gametes to the fertilization site. Diagram shows human female reproductive tract. Sperm deposited in the vagina must penetrate the mucus in the cervix, pass through the uterine cavity and enter the oviduct. Here the sperm may be ‘stored’, awaiting ovulation, when they detach and ascend the oviduct. At this point they show a highly ‘energetic’, hyperactivated form of motility which enables them to penetrate the vestments that surround the oocyte (and may also be important for detachment from the lining cells in the isthmal region).3 Fertilization takes place in the upper part of the oviduct (ampulla), close to the ovary. Dashed arrows show paths of egg (red) and sperm (blue) to the site of fertilization. (B) Structure of a mammalian oocyte and the vestments, which the sperm must penetrate. The zona (grey), a glycoprotein matrix, surrounds the oocyte and forms a protective layer around the early embryo prior to ‘hatching’. The cumulus, composed of granulosa cells (blue) embedded in a matrix of hyaluronic acid (yellow), surrounds the zona and is a source of progesterone27 and NO•.1 Hyperactivated motility and enzyme activity enable the sperm to penetrate these layers. Sperm are shown penetrating the cumulus [1], undergoing acrosome reaction [2], penetrating the zona [3] and in the sub-zonal space [4], where fusion with the egg can occur. (C) Structure of a human sperm, Box shows the position of the Ca²⁺ store in the sperm neck region. (D) Mobilization of Ca²⁺ in human sperm by nitroxyl (HNO) which reacts with protein thiols and has effects that can resemble those of S-nitrosylation.28,31 Cells were bathed in a low Ca²⁺ medium so the response is largely due to mobilization of stored Ca²⁺. Δ fluorescence shows change in [Ca²⁺]_i monitored using Oregon Green BAPTA-1. Filled squares show mean response of ≈100 cells in the experiment. Colored lines show ten individual cell responses. (E) Model for coincidence detection by the Ca²⁺ store at the sperm neck region. Progesterone, probably by binding to a membrane surface receptor (not yet identified) activates Ca²⁺ influx through channels at the plasma membrane (green), Consequent elevation of [Ca²⁺]_i induces mobilization of stored Ca²⁺ by Ca²⁺-induced Ca²⁺ release (CICR). NO causes S-nitrosylation of key thiols causing modulation/sensitization of the Ca²⁺ release channel (yellow) of the Ca²⁺ store. In this model the Ca²⁺ release channel of the store (ryanodine receptor?) acts as a coincidence detector.

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