Nuclear receptors, retinoid-induced

Melatonin is an indole-derived anterior pituitary hormone that causes downstream inhibition of a-MSH-induced melanogenesis. Melatonin is antiamnesic, synchronizes circadian and circannual rhythms and is metabolized to 5-methoxytryptamine. Melatonin acts via GPCRs MT1 and MT2 (which both couple through Gai and cAMP decrease). MT1 may also couple via Gao and Gaq to activate PLC (and hence increase cytosolic Ca2+) and via G Gy activation of PLA2. Melatonin can further interact with nuclear receptor superfamily orphan retinoid receptors RZR/ROR. Melatonin fluctuates with a circadian rhythm and is elevated in blood during the night. Melatonin is accordingly of social importance in relation to shift work and jet-lag. Melatonin and 5-methoxytryptamine occur in some plants (Table 5.8). 

The discovery of nuclear RARs has introduced a novel method for evaluating the potential carcinostatic activity of a new retinoid [81,84-88], This can be done by measuring the ability of a retinoid either to bind to the RARs [84,85,87,88] or to induce activation of reporter genes via an RAR [81,86-88]. The affinity of retinoids for nuclear receptors in HL-60 cells appears to correlate well with anti-APL activity in vitro [94,95] as discussed in the next section. In general, a good correlation between retinoid carcinostatic activity and ability to bind to or activate retinoic acid receptors appears to exist. 

A number of other nuclear receptors have also been shown to bind and be activated by retinoids. For example, testicular receptor 4 (TR4) has recently been suggested to be a retinoid receptor, because the binding of both retinol and RA can induce conformational changes of TR4 leading to the activation of this receptor (Zhou et al. 2011). TR4 can either function as homodimer or heterodimerize with testicular receptor 2 (TR2) to function in spermatogenesis, hpid and hpoprotein regulation, and central nervous system development (Zhou et al. 2011). However, additional experiments are required to reveal the physiological and developmental implications of the activation of TR4 by retinoids, such as RA (Zhou et al. 2011). 

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