A FAMILY OF HUMAN PHOSPHODIESTERASES HOMOLOGOUS TO THE DUNCE LEARNINGAND MEMORY GENE-PRODUCT OF DROSOPHILA-MELANOGASTER ARE POTENTIAL TARGETS FOR ANTIDEPRESSANT DRUGS

We have isolated cDNAs for four human genes (DPDE1 through DPDE4) clos ely related to the dnc learning and memory locus of Drosophila melanog aster. The deduced amino acid sequences of the Drosophila and human pr oteins have considerable homology, extending beyond the putative catal ytic region to include two novel, highly conserved, upstream conserved regions (UCR1 and UCR2). The upstream conserved regions are located i n the amino-terminal regions of the proteins and appear to be unique t o these genes. Polymerase chain reaction analysis suggested that these genes encoded the only homologs of dnc in the human genome. Three of the four genes were expressed in Saccharomyces cerevisiae and shown to encode cyclic AMP-specific phosphodiesterases. The products of the ex pressed genes displayed the pattern of sensitivity to inhibitors expec ted for members of the type IV, cyclic AMP-specific class of phosphodi esterases. Each of the four genes demonstrated a distinctive pattern o f expression in RNA from human cell lines.