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Steroidal Sigma Receptor Ligands Affect Signaling Pathways in Human Spermatozoa¹

^a Institut für Pharmakologie, Freie Universität Berlin, D-14195 Berlin, Germany ^b Forschungslaboratorien der Schering AG, D-13342 Berlin, Germany

ABSTRACT

In human spermatozoa, Ca²⁺ entry is stimulated by progesterone or prostaglandin E₁ (PGE₁). The regulation of cation currents by progestins involves sigma receptors, and sigma binding sites are abundant in testis. We examined the effects of sigma ligands on human spermatozoa. Ca²⁺ entry induced by progesterone or PGE₁ was not altered by the sigma ligands haloperidol and ditolylguanidine. However, the steroidal sigma ligands RU 3117 and RU 1968 had distinct effects. Stimulation by RU 3117 resulted in activation and homologous desensitization of the sperm progesterone receptor but not of the PGE₁ receptor. Because haloperidol and ditolylguanidine did not affect RU 3117 and progesterone actions in spermatozoa, we conclude that sigma receptors are not involved. However, RU 1968 potently inhibited both the progesterone- and PGE₁-induced Ca²⁺ entry and acrosome reaction. At higher concentrations, RU 1968 also inhibited hormonal Ca²⁺ signaling in fibroblasts. Despite suppression of Ca²⁺ mobilization, inhibition of phospholipase C by RU 1968 was not observed. Furthermore, RU 1968 did not impair the binding of inositol-1,4,5-trisphosphate to its endoplasmic reticulum receptor. Because RU 1968 preferentially inhibits signaling pathways in spermatozoa, the future development of more selective drugs structurally related to RU 1968 may be a novel approach for pharmacological contraception.

FOOTNOTES

First decision: 3 November 1999.

¹ This work was supported by grants from Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie, the Deutsche Forschungsgemeinschaft, and the Fonds der Chemischen Industrie.

² Correspondence: Thomas Gudermann, Institut für Pharmakologie, Freie Universität Berlin, Thielallee 67-73, D-14195 Berlin, Germany. FAX: 49 30 8445 1818; guderman{at}zedat.fu-berlin.de

³ Current address: Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Fachbereich Humanmedizin, Karl-von-Frisch-Str. 1, 35033 Marburg, Germany.

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