Alternative titles; symbols
HGNC Approved Gene Symbol: PDE9A
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38): 21:42,653,621-42,775,509 (from NCBI)
Cyclic nucleotide phosphodiesterases (PDEs), which hydrolyze the intracellular second messengers cAMP and cGMP to their corresponding monophosphates, play an important role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Mammalian PDEs have been divided into families based on sequence similarity, substrate specificity, affinity, sensitivity to cofactors, and sensitivity to inhibitory drugs. See 171885.
By searching an EST database for clones with homology to the catalytic domain of PDE4B (600127), Fisher et al. (1998) identified a prostate cDNA encoding a novel PDE. Sequence comparisons revealed that outside the catalytic domain, the predicted 593-amino acid protein shared little or no sequence similarity with 8 previously identified PDE families. Therefore, they designated it PDE9A. Using Northern blots, Fisher et al. (1998) determined that PDE9A is expressed as an approximately 2-kb mRNA in all tissues tested, with the most abundant expression in spleen, small intestine, and brain. Recombinant protein displayed very high affinity cGMP-specific PDE activity.
Using trapped exons to screen a lambda-gt10 library of human fetal brain cDNA, Guipponi et al. (1998) cloned a full-length PDE9A cDNA. Four different transcripts deriving from alternative splicing of 5-prime exons and containing the 3-prime,5-prime-cyclic nucleotide phosphodiesterase signature motif were identified. Northern blot analysis revealed several mRNA species of approximately 2.4 kb with varying expression patterns and intensities in all tissues examined except blood. Guipponi et al. (1998) also cloned the mouse homolog of the human PDE9A2 transcript, pde9A2, which shares 93% and 83% amino acid and nucleotide sequence identity to human PDE9A2, respectively.
Soderling et al. (1998) identified mouse cDNAs encoding a PDE designated MMPDE9A1. The protein sequences of MMPDE9A1 and PDE9A (also known as HSPDE9A2) are 93% identical, although MMPDE9A1 lacks 60 amino acids in the putative regulatory domain. Fisher et al. (1998) considered MMPDE9A1 to be the mouse homolog of PDE9A, and suggested that the protein isoforms differ because of alternative splicing in the regulatory domain.
Lee et al. (2015) showed that cGMP-selective PDE9A is expressed in the mammalian heart, including in humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacologic inhibition protects against pathologic responses to neurohormones and sustained pressure-overload stress. PDE9A inhibition reversed pre-established heart disease independent of nitric oxide synthase (NOS; 163731) activity, whereas PDE5A (603310) inhibition required active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Lee et al. (2015) concluded that, unlike PDE5A, PDE9A can regulate cGMP signaling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggested potential as a therapeutic target.
Guipponi et al. (1998) determined that the PDE9A gene contains 20 exons spanning 122 kb.
By analysis of a somatic cell hybrid panel and by its inclusion in a previously mapped yeast artificial chromosome, Guipponi et al. (1998) mapped the PDE9A gene to chromosome 21q22.3, between TFF1 and D21S360.
Fisher, D. A., Smith, J. F., Pillar, J. S., St. Denis, S. H., Cheng, J. B. Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. J. Biol. Chem. 273: 15559-15564, 1998. [PubMed: 9624146] [Full Text: https://doi.org/10.1074/jbc.273.25.15559]
Guipponi, M., Scott, H. S., Kudoh, J., Kawasaki, K., Shibuya, K., Shintani, A., Asakawa, S., Chen, H., Lalioti, M. D., Rossier, C., Minoshima, S., Shimizu, N., Antonarakis, S. E. Identification and characterization of a novel cyclic nucleotide phosphodiesterase gene (PDE9A) that maps to 21q22.3: alternative splicing of mRNA transcripts, genomic structure and sequence. Hum. Genet. 103: 386-392, 1998. [PubMed: 9856478] [Full Text: https://doi.org/10.1007/s004390050838]
Lee, D. I., Zhu, G., Sasaki, T., Cho, G.-S., Hamdani, N., Holewinski, R., Jo, S.-H., Danner, T., Zhang, M., Rainer, P. P., Bedja, D., Kirk, J. A., Ranek, M. J., Dostmann, W. R., Kwon, C., Margulies, K. B., Van Eyk, J. E., Paulus, W. J., Takimoto, E., Kass, D. A. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 519: 472-476, 2015. [PubMed: 25799991] [Full Text: https://doi.org/10.1038/nature14332]
Soderling, S. H., Bayuga, S. J., Beavo, J. A. Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J. Biol. Chem. 273: 15553-15558, 1998. [PubMed: 9624145] [Full Text: https://doi.org/10.1074/jbc.273.25.15553]