Stimulation of tyrosine phosphorylation by progesterone and its 11-OH derivatives: Dissection of a Ca2+-dependent and a Ca2+-independent mechanism

Progesterone has previously been shown to exert non-genomic effects on huma n spermatozoa by opening plasma membrane ion channels and by stimulating pr otein tyrosine phosphorylation. Here we examined how these two activities a re influenced by Il-hydroxyl substitution of the steroid molecule either in the alpha- or in the beta-configuration. Both the 11 alpha-OH and the 11 b eta-OH derivatives of progesterone were more effective than progesterone in stimulating tyrosine phosphorylation, although 11 alpha-OH-progesterone wa s a markedly weaker Ca2+-influx inducing agonist than the other two steroid s. In Ca2+-containing medium, the agonist activity of the 11 alpha-OH deriv ative was weaker than that of the 11 beta-OH derivative, and it was complet ely abolished by genistein, whereas that of progesterone and its 11 beta-OH derivative was inhibited only partly by this drug. In contrast, when appli ed in Ca2+-free medium, the 11 alpha-OH derivative was the strongest of the three agonists tested, and the effects of all the three steroids were comp letely abolished by genistein. These data show that the structural motifs o f steroid molecules that are responsible for the stimulation of tyrosine ph osphorylation are different from those mediating the steroid action on Ca2 influx through plasma membrane channels. The synthesis of selective agonis ts of both activities may lead to the development of new pharmacological ag ents to be used in the treament of steroid-dependent pathologies. (C) 1999 Academic Press.