A New Family of Steroid Receptors

Abstract

Zhu et al. cloned, expressed, and characterized a plasma membrane progestin receptor implicated in fish oocyte maturation. Although steroid hormones have classically been considered to act through nuclear receptors that act as transcription factors, some of their effects occur too rapidly to depend on transcriptional activation and appear to be initiated at the plasma membrane. The identification of plasma membrane steroid receptors, however, has remained elusive. Zhu et al. immunized mice with a partially purified progestin receptor preparation and created hybridomas that produce monoclonal antibodies from their splenocytes. The authors used antibodies that enabled progestin binding in a receptor capture assay to screen a sea trout ovarian expression library. Structural analysis of a cDNA clone thus identified predicted a plasma membrane protein with seven transmembrane domains. Northern analysis indicated that the putative receptor (mPR) was expressed in reproductive and neuroendocrine tissues; Western analysis combined with immunocytochemistry demonstrated plasma membrane localization in sea trout oocytes. Recombinant mPR showed specific, high-affinity progestin binding. Progestins inhibited adenosine 3′,5′-monophosphate (cAMP) production and stimulated phosphorylation of extracellular signal-regulated kinases 1 and 2 in transfected mammalian cells. The effect on cAMP was sensitive to pertussis toxin, which suggests that mPR may couple to a heterotrimeric guanosine triphosphate (GTP)-binding protein. mPR protein expression in sea trout oocytes was sensitive to hormonal stimulation and varied with maturation state; antisense analysis in zebrafish oocytes further suggested a role for mPR in oocyte maturation. In a related paper, this group cloned and partially characterized homologous genes from humans and several other species. Structural and phylogenetic analyses suggested that they comprised three groups in a novel family of membrane-associated steroid receptors. Hammes commented on this research, and proposed a model for nongenomic progestin signaling that encompassed both the classical steroid receptor and the mPR. Y. Zhu, C. D. Rice, Y. Pang, M. Pace, P. Thomas, Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc. Natl. Acad. Sci. U.S.A. 100 , 2231-2236 (2003). [Abstract] [Full Text] Y. Zhu, J. Bond, P. Thomas, Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc. Natl. Acad. Sci. U.S.A. 100 , 2237-2242 (2003). [Abstract] [Full Text] S. R. Hammes, The further redefining of steroid-mediated signaling. Proc. Natl. Acad. Sci. U.S.A. 100 , 2168-2170 (2003). [Full Text]