No abstract

We have isolated cDNAs for four human genes (DPDE1 through DPDE4) closely related to the dnc learning and memory locus ofDrosophila melanogaster. The deduced amino acid sequences of the Drosophila and human proteins have considerable homology, extending beyond the putative catalytic region to include two novel, highly conserved, upstream conserved regions (UCR1 and UCR2). The upstream conserved regions are located in the amino-terminal regions of the proteins and appear to be unique to 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 expressed genes displayed the pattern of sensitivity to inhibitors expected for members of the type IV, cyclic AMP-specific class of phosphodiesterases. Each of the four genes demonstrated a distinctive pattern of expression in RNA from human cell lines.Regulation of cyclic AMP (cAMP) is important in central nervous system (CNS) function in both invertebrates and mammals. Studies of two different invertebrates in particular have demonstrated a role for cAMP in learning and memory. InAplysia snails, long-term facilitation of neurons in the gill retraction reflex occurs with learning. These neuronal changes are associated with alterations in activity of several components of the cAMP signalling pathway, particularly adenylyl cyclase and a cAMP-dependent protein kinase (32). In Drosophila melanogaster, numerous mutations in genes affecting learning have been isolated, including dunce (dnc), which encodes a cAMP-specific phosphodiesterase (PDE), and rutabaga (rut), which encodes a calcium-calmodulinstimulated adenylyl cyclase (10,16,28). Electrophysiologic studies of neurons from dnc-and rut-flies have shown alterations in synaptic plasticity, suggesting that the functional changes occurring in learning in wild-type flies are similar to those seen in Aplysia snails (40). These observations suggest that modulation of the cAMP pathway can influence learning and memory in organisms widely separated in evolution.Evidence for a functional role of dunce-like PDEs in the mammalian CNS initially came from the development of specific inhibitors. Inhibitors of cAMP-specific PDEs, including the drug rolipram, have clinical activity as antidepressants (11). The initial biochemical analysis of mammalian CNS PDEs, and of these inhibitors, was limited to testing in partially purified preparations, which can contain multiple PDE isoforms (1). More recently, cDNAs for homologs of dnc have been cloned from rats (5,7,9,(36)(37)(38) and shown to be rolipram sensitive (14,37,38

No abstract

This work was supported by the Foundation for Reproductive Medicine, New York, New York, USA, a not-for-profit research foundation and intramural grants from the Center for Human Reproduction (CHR)-New York. N.G. and D.H.B. are members of the board of the Foundation for Reproductive Medicine. N.G. is owner of CHR-New York, where the study was conducted. N.G. and D.H.B. have been recipients of research awards, travel grants and speaker honoraria from various pharmaceutical and medical device companies. None of these companies was, however, in any way associated with the materials and the manuscript presented here. N.G. and D.H.B. are listed as co-inventors on a number of awarded and still pending U.S. patents, none related to the materials presented here. N.G. is on the board of a medically related company, not in any way associated with the data presented here.