Rapid Actions of Steroid Receptors in Cellular Signaling Pathways
Steroid hormones control diverse processes in reproduction and development. In target cells, they diffuse through the plasma membrane and bind to cytoplasmic receptors that mediate their action. Upon hormone binding, the steroid receptors undergo a conformational change and translocate to the nucleus, where they bind discrete nucleotide sequences to enhance the expression of specific genes. Steroid receptors also negatively regulate gene expression by binding to and down-regulating the activity of distinct transcription factors involved in cell proliferation, differentiation, and programmed cell death. Because all these responses require nuclear localization of the receptors, they are termed genomic functions, and they require about 30 to 60 minutes. These regulatory properties of steroid hormones can be distinguished from more rapid actions (<10 minutes) reminiscent of the activities of peptide hormones in the activation of signal transduction cascades. The mechanisms involved in initiating the rapid responses are still unclear, but they range from contributions of unidentified receptors to the involvement of heterotrimeric guanosine triphosphate-binding proteins (G proteins), or even the classical steroid receptors. Considerable advances have been made recently in the elucidation of the rapid responses mediated by steroid receptors. Accumulating evidence shows that a small but significant percentage of the conventional steroid receptors reside at the plasma membrane after ligand binding. From this location, they trigger diverse signaling cascades needed for cell proliferation and other biological processes. The effector molecules activated by the steroid receptors include mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC). Thus, steroid receptors integrate classical functions as transcription factors in the nucleus with functions as signaling molecules at the plasma membrane. These two properties together make up the entire repertoire of regulatory functions so far attributed to steroid hormones.