Membrane initiated steroid signaling (MISS): Computational, in vitro and in vivo evidence for a plasma membrane protein initially involved in genomic steroid hormone effects

Steroid hormones are indispensable for control of vital processes, development, reproduction and modulation of behavior. Lack or complete dysfunction of glucocorticoid (GC) signaling, in particular, have lethal consequences. Even a minor change in the level of circulating cortisol can be of physiological and clinical significance. Analysis of the action mechanisms of GC is therefore of major importance, especially since natural and synthetic GC are widely used in the therapy of GC-responsive diseases. According to the classical genomic concept of steroid hormone action, the effects of GC are mediated by specific nuclear receptors (GR). Recent findings provide evidence for the existence of additional, plasma membrane (PM) located steroid receptors, which are thought to be responsible for rapid, non-genomic responses. We present evidence for a PM-residing protein, termed “steroid hormone recognition and effector complex” (SHREC), which plays a pivotal role in the complex network of PM-related non-genomic responses leading to GR-mediated genomic effects. This conclusion was drawn from studies using different in vitro and in vivo models of a GC-target: (1) highly purified fractions of osmotically active PM-vesicles isolated from rat and human hepatocytes, (2) a computational model of SHREC generated by the “automated receptor modeling” (ARM) method, (3) rat liver cell lines transfected with a GC-responsive reporter gene construct and (4) young women orally administered with selected steroids. We conclude that SHREC and the GR participate in the same signaling chain, SHREC ↔ steroid interaction is the initial step and an interdependent part of the complete GC signal propagation, thus called “membrane initiated steroid signaling” (MISS).