Steroidal sigma receptor ligands affect signaling pathways in human spermatozoa

In human spermatozoa, Ca2+ entry is stimulated by progesterone or prostagla ndin E-1 (PGE(1)). The regulation of cation currents by progestins involves sigma receptors, and sigma binding sites are abundant in testis, We examin ed the effects of sigma ligands on human spermatozoa. Ca2+ entry induced by progesterone or PGE(1) was not altered by the sigma ligands haloperidol an d ditolylguanidine, However, the steroidal sigma ligands RU 3117 and RU 196 8 had distinct effects. Stimulation by RU 3117 resulted in activation and h omologous desensitization of the sperm progesterone receptor but not of the PGE(1) receptor. Because haloperidol and ditolylguanidine did not affect R U 3117 and progesterone actions in spermatozoa, we conclude that sigma rece ptors are not involved. However, RU 1968 potently inhibited both the proges terone- and PGE(2)-induced Ca2+ entry and acrosome reaction. At higher conc entrations, 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 o f inositol-1,4,5-trisphosphate to its endoplasmic reticulum receptor. Becau se RU 1968 preferentially inhibits signaling pathways in spermatozoa, the f uture development of more selective drugs structurally related to RU 1968 m ay be a novel approach for pharmacological contraception.