Disease relevance of PDE1

• Vibrio fischeri, a marine bacterium that forms a bioluminescent symbiosis with certain fish and squids, exhibits the unusual attribute of growth on 3':5'-cyclic AMP (cAMP), apparently through the activity of a 3':5'-cyclic nucleotide phosphodiesterase (3':5'-CNP) with exceptionally high activity [1].
• The pde1 gene, which encodes a protein homologous to S. cerevisiae cAMP phosphodiesterase I, was isolated as a multicopy suppressor of the sterility caused by a high cAMP level [2].

High impact information on PDE1

• Members of the first class of cDNAs also suppress the heat shock-sensitive phenotype of pde1- pde2- strains and encode cAMP phosphodiesterases [3].
• These results indicate a specific role for Pde1 in controlling glucose and intracellular acidification-induced cAMP signaling [4].
• In vitro phosphorylation of Pde1 resulted in a modest and variable increase in activity, but only in crude extracts [4].
• We show that Pde1 is rapidly phosphorylated in vivo upon addition of glucose to glycerol-grown cells, and this activation is absent in the Pde1(ala252) mutant [4].
• A mutation (pde1) was detected by suppressor activity on the CYR3 mutation which caused cAMP requirement for growth at 35 degrees C by the alteration of cAMP-dependent protein kinase [5].

Biological context of PDE1

• High-copy-number plasmids containing either PDE1 or PDE2 can reverse the growth arrest defects of yeast cells carrying the RAS2(Val-19) mutation [6].
• Human cyclic GMP-stimulated 3',5'-cyclic nucleotide phosphodiesterase (PDE2A3) cDNAs were cloned from hippocampus and fetal brain cDNA libraries [7].
• Experiments using cycloheximide, a general inhibitor of translation, allow to exclude the possibility of a futile cycle of Pde1 synthesis and degradation [8].
• The deduced amino acid sequence of the CpdP protein exhibited 30.3% identity with that of the low-affinity 3':5'-CNP (PDE1) of Saccharomyces cerevisiae and 33.6% identity with that of the extracellular 3':5'-CNP of Dictyostelium discoideum [1].
• The pde1/cgs2 gene encoding this protein has been previously identified, and studies have shown that deletion of this gene results in elevated levels of intracellular cAMP and inhibition of meiosis [9].

Anatomical context of PDE1

• We recently reported the isolation of a cDNA clone that encodes a human monocyte low-Km, rolipram-sensitive, cAMP PDEase (isozyme IV) [10].
• The V. fischeri 3':5'-CNP is located in the periplasm, a novel cellular location for this enzyme in bacteria [1].

Associations of PDE1 with chemical compounds

• We show that deletion of PDE1, but not PDE2, results in a much higher cAMP accumulation upon addition of glucose or upon intracellular acidification [4].
• Three of the six RAS2Val19 suppressors could suppress the deletion of PDE1 and PDE2, the cAMP phosphodiesterase (Pde)-encoding genes, suggesting that they act downstream from adenylyl cyclase (Cyr) [11].
• In addition, the enzymatic activity of HSPDE1B1 was inhibited by phosphodiesterase inhibitors with potencies similar to that displayed toward the bovine PDE1 enzymes: IBMX approximately equal to 8-methoxymethyl-IBMX > vinpocetine approximately equal to zaprinast > cilostamide > rolipram [12].

Other interactions of PDE1

• PDE1 and PDE2 appear to account for the aggregate cAMP phosphodiesterase activity of S. cerevisiae [6].
• Therefore P-28-24C is fortuitously a pde1 pde2 cyr1 triple mutant [13].
• A reduced cAMP level resulting from multiple copies of the PDE1 gene caused increased expression of the ENA1/PMR2 gene in response to high NaCl [14].
• These data provide evidence that fluctuations in cAMP levels are modulated by both Pka1-dependent regulation of Pde1 and another target that comprise a robust negative feedback loop to tightly constrain intracellular cAMP levels [15].

Analytical, diagnostic and therapeutic context of PDE1

• In addition, this activity profile closely follows the Pde1 protein level as judged from Western blotting with antibodies directed against Pde1 [8].

References