BERN.1 Friday, Jan. 4 Nonclassical steroid actions mediated by novel membrane receptors: lessons from studies in fish. THOMAS, Peter; University of Texas at Austin firstname.lastname@example.org
Although there is extensive evidence that steroids can exert rapid, nongenomic (i.e. nonclassical) actions initiated at the cell surface by binding to specific membrane steroid receptors (mSRs), their identities remain unclear. Recently we discovered the identities of two novel families of mSRs unrelated to nuclear receptors that are intermediaries in nonclassical progestin and estrogen actions. The progestin membrane receptor (mPR) was discovered in fish ovaries and comprises at least three subtypes, named alpha, beta and gamma. All three subtypes are present in fish and mammals and appear to have important roles in reproduction. Recent studies show the mPRs are intermediaries in progestin induction of oocyte maturation and stimulation of sperm hypermotility in fish. In mammals, the mPRs have been implicated in progesterone regulation of uterine function in humans and GnRH secretion in rodents. The estrogen membrane receptor is the orphan G protein coupled receptor (GPCR) GPR30, which had previously been shown to be involved in estrogen signaling in breast cancer cells and is also present in fish ovarian follicles. Recombinant and wildtype mPRs and GPR30 have ligand binding characteristics typical of steroid membrane receptors. Protein structure modeling indicates that both the mPRs and GPR30 have 7-transmembrane domains typical of GPCRs, but show no structural similarities at the amino acid level. Phylogenetic analysis suggests that both the mPRs and GPR30 were present early in vertebrate evolution, but have different bacterial origins. Both classes of receptors are directly coupled to G proteins and activate them upon treatment with their steroidal ligands. These findings suggest that steroid-initiated signaling pathways involving G protein activation arose multiple times during chordate evolution.