Principles of Signaling by Nuclear Receptors

Signal transduction by nuclear receptors is shown schematically in fig. 4.4. The natural hgands of nuclear receptors are lipophilic hormones that can enter the cell in a passive manner. A transmittance of the signal at the cell membrane, is not necessary, as is the case in the signaling via transmembrane receptors. Once inside the cell the hormone 

A detailed review of the structure and function of nuclear receptors is foimd in Man-gelsdorf et al. (1995) Beato et al. (1995) Kastner et al. (1995), Mangelsdorf and Evans (1995), Perlman and Evans, 1997). 

The nuclear receptors are localized in the cytosol or nucleus. Due to their hpophihc nature the natural ligands of the nuclear receptors can cross the cell membrane in a passive marmer and bind the cognate receptor in the cell interior. Binding by hormones activates the transcription regulatory effect of the receptor. 

In order to distinguish nuclear receptors from membrane-bound receptors, the former are sometimes referred to as soluble receptors. They can be found in the cytoplasm or nucleus. Their regulatory function is always performed, however, in the nucleus. 

In comparison to signaling pathways which utilize transmembrane receptors (see chapter 5, 8,11), signahng via nuclear receptors is of relatively simple structure. The pathways lead directly, with only a few participating protein components, from the extracellular space to the level of the DNA in the nucleus. Most important protein components of the signal pathway are known and well characterized. Nevertheless, we understand very little of the mechanism by which the activated receptors lead to a transcription initiation. This is due to the extreme complexity of transcription initiation in eucaryotes (see 1.2). Both the variety of proteins involved in the formation of a competent initiation complex, as well as the influence of chromatin structure, make it difficult to elucidate the exact function of nuclear receptors in transcription initiation. 

Apart from the classical, well-known hormones listed in Fig. 4.1, other compounds are also used as signaling ligands for the activation of certain nuclear receptors. These ligands may be synthesized intracellularly as normal metabolites such as fatty acids and bile acids and they may be derived from foreign lipophilic substances like drugs. 

The cognate receptors, e.g., the PPAR and the FXR, are quite promiscuous with respect to the nature of the ligand and have been shown to be able to bind a broad range of lipophilic ligands. This type of receptors is thought to be involved in the homoostasis of metabolism and in the detoxification of foreign substances. 

Signaling via nuclear receptors is paramount for the development and differentiation of higher organisms, since these processes do not require a rapid response but do 

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