Receptor nuclear

Receptors are traditionally subdivided into nuclear receptors and cell surface receptors. The two groups of receptors are considered separately in the following discussions. 

The superfamily of regulatory proteins that interacts with hormones such as cortisol, the sex steroids estradiol and testosterone, thyroxine and with 

Increased cortisol suppression and insulin sensitivity Mineralocorticoid resistance 

Arg641 Val missense mutation creates receptor with decreased affinity for dexamethasone (24) 

Splice site deletion creates reduced receptor abundance (55) 

The nuclear receptor is an intrinsic chromosomal acidic non-histone protein whose localization in the nucleus is not dependent on the presence of the hormone. It can be extracted by salts [36] yielding a 3.5-3.8 S [37] protein having a molecular mass 

Affinity labelling of thyroid hormones to nuclear receptors indicated the presence of an abundant 47000 Da component and a less abundant 57000 Da species [40], Micrococcal nuclease also excises the two receptor forms. It is yet not clear whether these two forms are products of different genes or if the 57 000 Da form is converted or processed to the 47 000 Da species. 

Nuclear receptors, which bind triiodothyronine (T3) after it enters the cell  

Cytosolic receptors, which bind steroid hormones as they diffuse into the cell and 

Cell surface receptors, which detect water-soluble hormones that do not enter the cell (peptides, proteins, glycoproteins, catecholamines). The mechanism of action of each of these receptor types is different because each is associated with different postreceptor events in the cell. 

Toxicologically the function of the terminal hormones of endocrine cascades (i.e., steroid, retinoid, thyroid hormones) appear to be most susceptible to disruption by chemicals. This is because many foreign molecules share sufficient characteristics with these hormone molecules to allow binding to the nuclear receptors of these hormones in either an agonistic or antagonistic fashion. The binding of the xenobiotic to the 

Note Recognition sequences are split by spacer nucleotides, 

In contrast to the steroid receptor family, members of the thyroid receptor family typically do not associate with accessory proteins and are not localized to the extranucleus matrix. Rather, these receptors exist in the basal state associated with chromatin in the cell nucleus. When bound by hormone ligand, thyroid receptor family members dissociate from the chromatin and typically form heterodimeric combinations with the retinoid-X receptor (RXR). RXR also is capable of homodimerization in association with its ligand 9-cis retinoic acid. Thus high 9-cis retinoic acid levels apparently promote homodimerization, and low levels are permissive of heterodimerization of RXR with activation by the partner ligand. 

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Fig. 2. Early events in thyroid-hormone action. Interaction of T with cell nuclear receptors (6).

AE Sluder, SW Mathews, D Hough, VP Ym, CV Mama. The nuclear receptor superfamily has undergone extensive proliferation and diversification in nematodes. Genome Res 9 103-120, 1999. 

In summary, a DNA-supported asymmetric interface located within the DNA-binding domains of these nuclear receptors provides the molecular basis for receptor heterodimers to distinguish between closely related response elements. RXR can provide a repertoire of different dimerization surfaces, each one unique for a specific partner, allowing dimers to form that are adapted to the length of the spacer region in their corresponding response elements. 

Figure 10.12 Response elements for heterodimers of the nuclear receptor for ds-retinoic acid (RXR) with the receptors for vitamin D (VDR), thyroid hormone (TR) and trans-retinoic acid (RAR). The half-sites of these response elements have identical nucleotide sequences and are organized as direct repeats. They differ in the number of base pairs in the spacer region between the half-sites. This difference forms the basis for the ability of the heterodimers to discriminate between the different response elements.

Rastinejad, E, et al. Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature 375 203-211, 1995. 

The thiazolidinediones have also been reported to act as inhibitors of the respiratory chain at high concentrations, and this appears to account for their ability to activate AMGPK in cultured cells. However, the primary target of the thiazolidinediones appears to be the peroxisome proliferator-activated receptor-y ( PPAR-y), a member of the nuclear receptor superfamily expressed in adipocytes. One of the major effects of stimulation of PPAR-y in adipocytes is the release ofthe... 

Francis GA, Fayard E, Picard F et al (2003) Nuclear receptors and the control of metabolism. Annu Rev Physiol 65 261-311... 

Houten SM, Auwerx J (2004) The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts. Ann Med 36 482-491... 

Macromolecules that associate with nuclear receptors to modulate their transcriptional activity. 

Another example is a recently discovered second mode of action by which nuclear receptors modulate transcription. In contrast to DNA-binding-dependent mechanisms, cross talk refers here to gene regulation by protein-protein-interaction of nuclear receptors with other transcription factors, such as AP-1 or NF-kB. Consequently, the nuclear receptor acts as a corepressor or coactivator of transcription. 

Transmembrane Signalling Nuclear Receptors Gluco-mineralocorticoid Receptors... 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes... 

Glucocorticoid Receptor GR GCR GRL Nuclear Receptor Subfamily 3, Group C, Member 1 (NR3C1) Glucocorticoid Receptor Type II Mineralocorticoid Receptor MR MCR MRL Nuclear Receptor Subfamily 3, Group C, Member 2 (NR3C2) Glucocorticoid Receptor Type I Aldosterone Receptor... 

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