Androgen and estrogen signaling at the cell membrane via G-proteins and cyclic adenosine monophosphate

Androgens and estrogens are well-known to initiate their actions by binding to specific intracellular receptors. The steroid–receptor interaction, the receptors, and the details of transcriptional activation consequent to the binding of these steroids with their respective receptors have been, and continue to be, intensively studied. More recently, it has become increasingly apparent that steroids may interact with cells by other than this classic pathway. This communication will deal with activation by sex hormones of a signal transduction pathway that originates at the cell membrane and utilizes cyclic adenosine monophosphate (cAMP) as a second messenger. The system consists of three components, an agonist steroid, sex hormone-binding globulin (SHBG), and a membrane receptor (R SHBG) for SHBG. SHBG is a well-characterized plasma protein that has two binding sites, one binds certain estrogens and androgens, and the other binds to R SHBG. The characteristics of this novel signal transduction system, from the interaction of SHBG with R SHBG, to the intermediacy of G-proteins, to cAMP generation, to downstream effects of the second messenger will be reviewed.