The main discoveries of the Genetic Pharmacology Unit during FY 93 were the following: (1) Transcriptional regulation of the D1A dopamine (DA) receptor gene: We had previously localized the main enhancer of the human D1A gene between nucleotides -1342 and -1102 relative to the first ATG codon. In FY 93, we found that most of this enhancer activity is between -1154 and -1137 and some also between -1197 and -1155. We determined that this enhancer interacts with multiple nuclear proteins as complexes to activate the promoter. Although the sequences protected by these complexes include AP2 binding sites, we discovered that AP2 is not involved in positively modulating the basal expression of the D1A gene. The complex at the main enhancer includes at least two proteins one of which is antigenically related to Sp1 or is Sp1 itself. (2) Promoter analysis of the D2 DA receptor gene: During FY 93, we focused on the silencer of the rat D2 gene which we had previously localized between nucleotides -217 and -75. An Sp1 consensus sequence and a TGGG repeat in this silencer interact with a complex of two proteins one of which is Sp1. We also discovered that most of the silencing activity is actually localized between -160 and -135 although thus far no in vitro DNA-protein interaction has been detected in this region. (3) Analysis of the 5' flanking region of the D3 DA gene: Toward our efforts to characterize the 5' flanking region of the rat D3 gene, we cloned and sequenced its true exon I. We found that unlike the D2 gene, the D3 exon I is only 50% G+C rich, although the two genes are highly homologous in their coding region. Using the new sequence information, we cloned a genomic fragment including the upstream region of the D3 gene. (4) Genetic regulation of the rat BDNF gene: During our efforts to clone the most upstream exon in the rat BDNF gene, we discovered that there are at least five different first exons alternatively spliced with a common coding exon II. Each of these first exons appear to be transcribed from an alternate promoter that may be active in a brain region-specific manner. (5) Regulation of POMC gene transcription: We localized a CRH responsive region between -141 and -106 relative to transcription start site in the mouse POMC gene. The second messenger systems transducing this signal-transcription coupling appeared not to exert their actions solely through PKA or PKC. (6) Protection against neuronal degeneration: We discovered that an adenosine A1 agonist protects against and restores MPTP-induced striatal dopamine depletion in rats.
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