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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Henry Niman who wrote (12884)	12/31/1997 12:59:00 AM
From: Flagrante Delictu	Read Replies (1) \| Respond to of 32384

Henry,>>Activationof the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family<<. I am very greatful to Miljenko Zuanic for his recent post about the abstract of the article in PNAS. The conclusion that the recent finding assigns to retinoids an" important role in the control of gene expression in the central nervous system" rivals the unexpected findings 2 years ago in the metabolic arena. In the full article in PNAS, for those who haven't had a chance to peruse it, I got excited by learning that Dopamine {DA} is one of the major neuromodulators in the central nervous system{CNS}, controlling key physiological functions from coordination of movements to hormone synthesis & secretion. They investigated the DA D2 receptor {D2R} which is highly expressed in the CNS & in the pituitary gland, & concluded it had a key role not only in mediating events in the target cells of dopaminergic neurons but also in contolling the release of DA. Further testing led to the conclusion that the control of the expression of the D2R gene must involve cell-specific transcription factors. Then they showed that the transcription of the D2R gene is induced upon treatment of pituitary cells with retinoids. They defined" the/a promoter fragment that is responsible for retinoic acid {RA} inducibility in transfected cells. A functional RA-response element {RARE} is present in the D2R promoter that readily binds retinoic acid receptor/retinoid-RXR} heterodimers." They state that"importantly,D2R trancripts are reduced in striatal tissue from certain RAR-& RXR-null mice, thus revealing a novel role for retinoids in the regulation of CNS functions". More in next response. Bernie.

To: Henry Niman who wrote (12884)	12/31/1997 1:53:00 AM
From: Flagrante Delictu	Respond to of 32384

Henry,>continuing my prior missive on the D2R receptor<< They went on to mention that "these results indicate that the RARE-like site present in the D2R promoter responds to the presence of RA, through the binding of the RAR-RXR heterodimers, with no apparent significant preference for particular RAR isotypes." They found that RARa & RXRa individually bind poorly to the D2R RARE, whereas the presence of both receptors greatly enhances D2R RARE binding because of the higher affinity of RAR-RXR heterodimers to a RARE. One can see why they state that ' Our results strongly suggest the RARs regulate D2R gene transcription." Their final discussion was lengthy. The highlights, IMO, were "Alterations in the dopaminergic system in humans result in mental diseases such as schizophrenia & Parkinson's disease. {Someone please point this out to Courtney Willfore.} Their "observations suggest that gene regulation of dopamine receptors, & in particular of the D2R, is a key element in the normal function of the dopaminergic system. ... In this paper, we demonstrate that RAR-RXR heterodimers bind to this motif {of the D2R RARE} & activate transcription from the D2R promoter. ... It should be pointed out that the D2R is expressed in different regions of the brain & in particular by the dopaminergic cells in mesencephalic {IYWPTE} neurons & by the dopaminergic neuron targets, such as the medium spiny neurons in the striatum, but also by cortical & hypothalmic cells. In addition, outside the brain the D2R is highly expressed in the pituitary gland by 2 cell types, melantrophs & lactotrophs. It is thus conceivable that the D2R promoter might be controlled by different combinations of members of the thyroid hormone/RA & vitamin D3 receptor families in different cell types. However, our results point to a crucial role of members of the RAR & RXR families in the control of D2R expression in the striatum. This control is dependent on the binding of RAR-RXR heterodimers as demonstrated by the stronger decrease of D2R expression in RAR-RXR double mutants as compared with single mutants. This suggests that absence of one retinoid receptor might be partially compensated by other members of the RAR-RXR family in single mutants. These results strongly support our in vitro data & identify these receptors as specific transcription factors required for full expression of the D2R gene in the striatum. Our data indicate an involvement of RA in adult CNS functions, as absence of retinoid receptors results in a reduced expression of the DA D2 receptor. We have previously shown that ,in mice, altered expression of this receptor results in a parkinsonian phenotype & pituitary tumors. It is well established that Parkinson's disease is generated by a strong reduction of DA levels. Our data raise the possibility that aberrant control of dopaminergic receptor expression m ight also lead to neurological disorders." Bernie. Abbreviations Ra,retinoic acid; RAR, RA receptor;RXR,retinoid X receptor; DA, dopamine;D2R, dopamine DR receptor;RARE, RA response element; CNS, central nervous system.