In closing, we would like to borrow the "unfolding of a continuing concept" formulated by C. Szego (41) many years ago and in a timely recent review (53), to summarize what we have discussed in this chapter. According to the unfolding of the continuous process, E initially faces the extracellular compartment of the cell membrane as depicted in Fig. 20. For a more detailed discussion, the readers are referred to a recent review of us (1). At least, we can distinguish three major initial events corresponding to three distinct pathways: first, the classical diffusion pathway by which E will diffuse inside the cell to bind the nER in an inactive state. The binding dissociates heat shock proteins and E-receptor dimers find its way to the ERE in the DNA to activate gene transcription (54). This intracellular E could also diffuse inside the membrane of the mitochondria to encounter the OSCP subunit of the ATP synthase (47) and thereby

Fig. 20. A model of the "unfolding of a continuum concept" taken and modified from Szego (41) of estradiol action at the cellular level. For details, see text.

regulate cell energy by altering ATP production (43,44); the second pathway involves an active endocytotic process, which has been initially reported for the uterus (55) but also recently detected in the hypothalamus and other brain cells (56-58). In this process, E is internalized by a translocation mechanism most likely involving an E receptor molecule with the formation of a receptosome that after enzymatic digestion by lysosomes (41) releases its receptor (which might be recycled) and the free E is then available for intracellular actions, including enzymatic degradation. Recently, we have presented evidence indicating that this process may be present in the liver of ovx adult rats, because in vivo administration of E-6-125I-BSA led to translocation of the ligand from the plasmalemma to the mitochondrial compartment within 5 min postinjection (59); the third pathway probably involves a receptor coupled to a G protein, which either activates an adenylate cyclase system with cAMP production (60-62) or a PLC system with secondary production of IP3 and DAG (63,64), two important intracellular messengers controlling intracellular distribution of calcium. Our data on E-6-BSA-evoked DA release from the CS most likely involves either of these two intracellular events.

In summary, in the search for a mER we have rediscovered the concept that E may bind to several unique proteins, either enzymes or typically known or novel receptors, in the regulation of specific cellular functions.

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