Retinoid x receptor

In 1991, Evans identified a receptor that was active in both fruit flies and mammals. This receptor reacted to retinoic acid. He called it the retinoid X receptor (RXR).

Like RAR, the retinoid X-receptor (RXR) belongs to the superfamily of nuclear receptors and plays a central role in cell differentiation (e.g. also in the therapy of acne with retinoids), organogenesis and neonatal development (Szanto A et al. 2004).

The retinoid X receptor RXR occurs in 3 isoforms RXRα, RXRβ/δ and RXRγ. The isoforms are formed by alternative splicing (Mangelsdorf DJ et al. 1992). RXRβ/δ is ubiquitously expressed. RXRγ is found mainly in the skeletal and cardiac muscles, the anterior pituitary gland and brain (Schuler MJ et al. 1998; McDermott NB et al. 2002). RXRα is expressed by kidney, liver and spleen tissue, the epidermis and the placenta. All three RXR isoforms are involved in cell proliferation, cell differentiation, embryonic patterning and organogenesis. Together with thymine DNA glycosylase, RXR contributes to DNA repair. Furthermore, RXR is able to promote apoptosis (Cao X et al. 2004).

RXR can act as a homodimer in the form of RXR-RXR or form heterodimers with other nuclear receptors. This process activates transcription (Kastner P 1995). Due to this affinity, the retinoid X-receptor is the crucial receptor in a multitude of signal transductions and is involved in numerous physiological processes as a multifunctional key receptor.

The natural ligand of RXR is 9-cis-retinoic acid (9-cisRA) (Heyman RA et al. 1992). It is important to note that 9-cisRA is much more potent in the activation of RXR than, for example, the isotypes all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13cisRA). Further ligands of RXR are the unsaturated fatty acid docosahexanoic acid (DHA) and the vitamin A derivative β-apo14'-carotenal (Collins MD et al. 1999).

Vitamin A has a significant influence on embryological development through activation of the RXR and RAR isoforms (RAR = receptor for all-trans-retinoic acid). Isotretinoin is introduced into the cell as a prodrug and isomerised to all-trans-retinoic acid. There it binds to the cellular retinal binding protein -2 (CRABP-2), is translocated into the cell nucleus and activates the corresponding RAR. This process leads to a proaptotic transcriptional change in the sebocytes. This process leads to a reduction of sebum, which reduces growth, biofilm formation and activity of P. acnes.

During embryo- and morphogenesis RAR acts as the main heterodimeric partner of RXRα. However, it is believed that RXR is involved in morphogenesis only through heterodimeric binding with RAR. Other heterodimeric partners of RXR such as PPAR, THR, VDR, LXR, PXR and CAR do not play an essential role in morphogenesis, since defects in these do not cause morphological abnormalities (Mark M et al. 2009). Thus, the relevance of RXRα during embryogenesis is demonstrated by the fact that "RXRα knock-out mice" die between the embryological day (E) E13.5 and E16.5 (Kastner P et al.1994).

Together with PPARγ, RXRα indirectly influences trophoblast differentiation in that the receptors regulate the secretion of gestational hormones such as hCG, lactogen and leptin. Furthermore, RXRα and PPARγ regulate the absorption of fatty acids in trophoblasts, which is essential for the production of steroid hormones in the placenta and further fetal development.

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3. Heyman RA et al (1992) 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68:397-406.
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