Molecular Mechanism for Human Sperm Chemotaxis Mediated by Progesterone

Maria E Teves,Hector A Guidobaldi,Laura C Giojalas,Diego R Uñates,Aduén A Morales Garcia,Stephen J Publicover,Raul Sanchez,Werner Miska,Immo A Hansen

doi:10.1371/journal.pone.0008211

Abstract

Sperm chemotaxis is a chemical guiding mechanism that may orient spermatozoa to the egg surface. A picomolar concentration gradient of Progesterone (P), the main steroidal component secreted by the cumulus cells that surround the egg, attracts human spermatozoa. In order to elucidate the molecular mechanism of sperm chemotaxis mediated by P, we combine the application of different strategies: pharmacological inhibition of signaling molecules, measurements of the concentrations of second messengers and activation of the chemotactic signaling. Our data implicate a number of classic signal transduction pathways in the response and provide a model for the sequence of events, where the tmAC-cAMP-PKA pathway is activated first, followed by protein tyrosine phosphorylation (equatorial band and flagellum) and calcium mobilization (through IP3R and SOC channels), whereas the sGC-cGMP-PKG cascade, is activated later. These events lead to sperm orientation towards the source of the chemoattractant. The finding proposes a molecular mechanism which contributes to the understanding of the signal transduction pathway that takes place in a physiological process as chemotaxis.

Highlights

One of the primary questions in reproductive biology concerns the mechanism(s) by which gamete encounter is achieved
There was a significant decrease in the percentage of cells showing pattern ‘‘H’’ only when the tmAC or Protein Kinase A (PKA) were inhibited (Figs. 5C and D). To further verify the latter result, spermatozoa were exposed to an extracellular gradient of dbcAMP or db-cGMP, where a significant increase in the percentage of cells with the specific pattern ‘‘H’’ was observed only upon stimulation with the cAMP analog, and at the same level as observed with 10 pM P (Fig. 5E). These results suggest a sequence for the chemotactic signaling activation starting with the tmAC-cAMP-PKA pathway, followed by protein Tyr-phosphorylation, calcium mobilization, and the activation of soluble guanylyl cyclase (sGC)-cGMP-Protein Kinase G (PKG) cascade, with a later second calcium influx
We recently showed that tiny amounts of P secreted by the cumulus cells chemoattract human and rabbit spermatozoa at pM concentrations [2], becoming the cumulus oophorus and its surrounding the probable site for sperm chemotaxis in vivo [2,3]

Summary

Introduction

One of the primary questions in reproductive biology concerns the mechanism(s) by which gamete encounter is achieved. The main steroid from all these attractant sources is Progesterone (P), which is secreted by the cells that surround the egg and forms a stable concentration gradient along the cumulus oophorus [2,3]. This hormone induces sperm chemotaxis mainly at very low concentrations (pM), only in a ,10% subpopulation of cells [4,5]. It seems to be the only physiological chemoattractant secreted by the cumulus cells [3]. Bourgeonal, a chemoattractant for which no endogenous equivalent has yet been identified, has been proposed to stimulate olfactory receptors (hOR17-4), leading to activation, via Golf of tmAC and Ca2+ influx [6]

Methods

Results

Conclusion