Molecular mechanism for human sperm chemotaxis mediated by progesterone

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

doi:10.1371/journal.pone.0008211

Molecular mechanism for human sperm chemotaxis mediated by progesterone

Teves ME, Guidobaldi HA, Uñates DR, Sanchez R, Miska W, Publicover SJ, Morales Garcia AA, Giojalas LC

Published December 8, 2009 PloS One, 4(12), e8211

DOI 10.1371/journal.pone.0008211 PMID 19997608 PMC PMC2782141

RRM Academy Synopsis

Human sperm turn toward progesterone through a proposed signal chain

A laboratory study of sperm from healthy donors suggests that progesterone steers human sperm through an ordered chain of internal signals. Researchers blocked signaling molecules one at a time and watched whether sperm still swam toward progesterone. The proposed order starts with cAMP and PKA signals, then calcium release, then cGMP.

Key Findings

Progesterone significantly raised intracellular cAMP. Inhibiting transmembrane adenylyl cyclase abolished chemotaxis (swimming toward a chemical source) without affecting motility, and a soluble adenylyl cyclase inhibitor had no effect.
PKA inhibition completely abolished chemotaxis toward progesterone at high inhibitor doses, with motility unaffected.
Progesterone significantly raised intracellular cGMP. Inhibitors of soluble guanylyl cyclase and of PKG suppressed chemotaxis with no significant effect on sperm motility.
Chelating intracellular calcium completely inhibited chemotaxis. Blockers of store-operated calcium channels and of IP3 receptors abolished it, while a ryanodine receptor blocker had no effect.
Under capacitating conditions, progesterone raised the share of sperm showing tyrosine phosphorylation in the equatorial band and flagellum by about 10%. A cAMP analog reproduced the rise; a cGMP analog did not.

Interpretation

The experiments used sperm from healthy donors with normal semen parameters. Each measurement came from three to six independent experiments. The order of steps is inferred from inhibitors and cyclic nucleotide analogs, and the authors call their model tentative. The authors advise caution in reading inhibitor results, including the role of IP3 receptors. They describe progesterone chemotaxis as limited to about 10% of sperm. The report gives no pregnancy outcomes.

RRM Context

Cells around the egg secrete progesterone. The model has sperm following a signal from the egg's own surroundings. Restorative reproductive medicine treats conception as a coordinated event between two partners. A hormone passing from egg-side cells to sperm illustrates that coordination at the cellular level.

Our editorial summary of this paper, not the article's abstract.

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 IP(3)R 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.

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

M Teves, H Guidobaldi, D Uñates, R Sanchez, W Miska, Steve Publicover, S Publicover, A Garcia, L Giojalas

PMID 19997608 19997608 DOI 10.1371/journal.pone.0008211 10.1371/journal.pone.0008211 Teves et al. 2009, Teves 2009

Keywords

Calcium Channels, Phosphotyrosine, Progesterone, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclic GMP-Dependent Protein Kinases, Adenylyl Cyclases, Guanylate Cyclase, Cyclic GMP, Calcium

Molecular mechanism for human sperm chemotaxis mediated by progesterone

Human sperm turn toward progesterone through a proposed signal chain

Key Findings

Interpretation

RRM Context

Abstract

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Keywords