HGNC Approved Gene Symbol: PDE8A
Cytogenetic location: 15q25.3 Genomic coordinates (GRCh38): 15:84,980,467-85,139,142 (from NCBI)
Phosphodiesterases (PDEs) regulate the intracellular levels of cAMP and cGMP. These cyclic nucleotides play an important role as second messengers in multiple physiologic processes, including regulation of vascular resistance, cardiac output, visceral motility, immune response, inflammation, neuroplasticity, vision, and reproduction. PDEs comprise a large superfamily of enzymes divided into 10 families. Different PDEs can be distinguished by their structure, tissue expression, localization, substrate specificity, regulation, and sensitivity to PDE inhibitors. Diversity in structure and specificity of function make PDEs promising targets for the pharmacotherapy of diseases modulated by cyclic nucleotide signaling (Hetman et al., 2000). See 171885.
By searching an EST database for clones with homology to the catalytic domain of PDE4B (600127), Fisher et al. (1998) identified apparently partial cDNAs encoding 713 amino acids of a novel PDE. Sequence comparisons revealed that the predicted catalytic domain shared only 20 to 39% sequence identity with those of 7 previously identified PDE families. Therefore, the authors designated the protein PDE8A. Using Northern blots, Fisher et al. (1998) determined that PDE8A is expressed as an approximately 4.5-kb mRNA in a wide variety of tissues. A recombinant protein containing the 545 C-terminal amino acids of PDE8A displayed very high affinity cAMP-specific PDE activity. Unlike PDE4 and PDE7, the other high affinity cAMP-specific PDEs, PDE8A was not inhibited by IBMX (3-isobutyl-1-methyl-xanthine).
Wang et al. (2001) cloned 5 PDE8A splice variants from testis and normal human T-cell cDNA libraries. The variants, called PDE8A1 through PDE8A5, share a common 5-prime sequence but differ from each other by the presence or absence of exons 7 through 9. Full-length PDE8A protein, which they called PDE8A1, has has 829 amino acids and a calculated molecular mass of 93.3 kD. It has an N-terminal REC domain and PAS domain and a C-terminal catalytic domain. It also contains several sites for protein phosphorylation, N-glycosylation, N-myristoylation, and amidation. Mouse Pde8a1 contains a nuclear localization sequence not found in human PDE8A1. PDE8A2 contains 783 amino acids and has a calculated molecular mass of 88.3 kD. PDE8A3 contains 449 amino acids and has a calculated molecular mass of 51.3 kD, and PDE8A4 and PDE8A5 encode identical 582-amino acid proteins with a calculated molecular mass of 66.0 kD. The isoforms differ from each other in the deletion or insertion of sequences in the PAS domains; PDE8A3 lacks the entire PAS domain. Only PDE8A1 and PDE8A2 were evaluated for tissue distribution. Real-time quantitative PCR detected both transcripts in all human tissues examined with expression levels of PDE8A1 much higher than that of PDE8A2. PDE8A1 and PDE8A2 showed highest expression in testis and spleen, respectively, and both showed lowest expression in skeletal muscle and bone marrow. By in situ hybridization of mouse testis, Vasta et al. (2006) showed Pde8a was expressed specifically in Leydig cells.
Wang et al. (2001) determined that the PDE8A gene contains 23 exons and spans over 80 kb. The 5-prime region of the PDE8A is GC-rich, and it contains a TATA box and numerous transcription factor binding sites, including some involved in cAMP-responsive transcriptional regulation and in expression of genes in T cells.
Wang et al. (2001) noted that the PDE8A gene maps to chromosome 15q25.3-q26.1.
Vasta et al. (2006) showed that knockdown of Pde8a in mice altered luteinizing hormone (LH; see LHB 152780) signaling and steroidogenesis. In Pde8a-knockout Leydig cells, they found a 4-fold increase in sensitivity to LH for testosterone production. They concluded that PDE8A plays a role in setting the sensitivity to LH for testosterone production
Fisher, D. A., Smith, J. F., Pillar, J. S., St. Denis, S. H., Cheng, J. B. Isolation and characterization of PDE8A, a novel human cAMP-specific phosphodiesterase. Biochem. Biophys. Res. Commun. 246: 570-577, 1998. [PubMed: 9618252] [Full Text: https://doi.org/10.1006/bbrc.1998.8684]
Hetman, J. M., Soderling, S. H., Glavas, N. A., Beavo, J. A. Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase. Proc. Nat. Acad. Sci. 97: 472-476, 2000. [PubMed: 10618442] [Full Text: https://doi.org/10.1073/pnas.97.1.472]
Vasta, V., Shimizu-Albergine, M., Beavo, J. A. Modulation of Leydig cell function by cyclic nucleotide phosphodiesterase 8A. Proc. Nat. Acad. Sci. 103: 19925-19930, 2006. [PubMed: 17172443] [Full Text: https://doi.org/10.1073/pnas.0609483103]
Wang, P., Wu, P., Egan, R. W., Billah, M. M. Human phosphodiesterase 8A splice variants: cloning, gene organization, and tissue distribution. Gene 280: 183-194, 2001. [PubMed: 11738832] [Full Text: https://doi.org/10.1016/s0378-1119(01)00783-1]