Alternative titles; symbols
HGNC Approved Gene Symbol: PDE4B
Cytogenetic location: 1p31.3 Genomic coordinates (GRCh38): 1:65,792,510-66,374,579 (from NCBI)
Cyclic nucleotides are important second messengers that regulate and mediate a number of cellular responses to extracellular signals, such as hormones, light, and neurotransmitters. Cyclic nucleotide phosphodiesterases (PDEs) regulate the cellular concentrations of cyclic nucleotides and thereby play a role in signal transduction. PDE4B is a class IV cAMP-specific PDE (summary by Milatovich et al., 1994).
Using RNA from a human lymphocytic B-cell line and a rat PDE IV member B probe, Obernolte et al. (1993) isolated a 3.8-kb cDNA. A single large open reading frame predicted a 564-amino acid protein with 92.9% identity to rat Pde4b; at the nucleotide level, the identity was 86.3%. They determined that a related cDNA clone isolated from human monocytes by Livi et al. (1990) was the human homolog of rat Pde4a (600126). Southern blot analysis indicated that distinct genes encode these 2 PDE IV family members.
Using degenerate primers based on Drosophila dnc and rat Dpd to amplify human Dpd orthologs, followed by low-stringency hybridization of a brain cDNA library, Bolger et al. (1993) cloned full-length DPDE4, which they called TM72, and a splice variant that differs in its 5-prime sequence, which they called PDE32. The deduced full-length DPDE4 protein contains 642 amino acids. It has 2 N-terminal domains that share a high degree of conservation with other DPDE proteins, and a C-terminal catalytic domain. The deduced PDE32 isoform differs from the full-length protein in its N-terminal region and lacks the first conserved domain. Screening a Northern blot of normal human temporal cortex with a full-length DPDE4 probe revealed transcripts of 4.6 and 4.0 kb. RNase protection assays detected full-length DPDE4 in glioblastoma and neuroblastoma cell lines, but not in 5 other cell lines examined.
Huston et al. (1997) cloned a novel human (and its cognate rat) PDE4B splice variant and compared its activities to the 2 other splice variants from this locus. Alternative splicing of mRNA generated from both the human and rat PDE4B genes produced long and short splice variants that had unique N-terminal regions. It was suggested that these alternatively spliced regions determined changes in the maximal catalytic activity of the isoforms, their susceptibility to inhibition by rolipram, and mode of interaction with particulate fractions.
Bolger et al. (1993) confirmed that full-length DPDE4 showed cAMP PDE activity, which was inhibited by several cyclin nucleotide PDE inhibitors.
Millar et al. (2005) reported that the PDE4B gene is disrupted by a balanced translocation in a subject diagnosed with schizophrenia (see 181500) and a relative with chronic psychiatric illness. The phosphodiesterases inactivate cAMP, a second messenger implicated in learning, memory, and mood. Millar et al. (2005) showed that DISC1 (605210) interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and in increase in PDE4B activity. Millar et al. (2005) proposed a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.
Xu et al. (2000) determined the 3-dimensional structure of the catalytic domain of phosphodiesterase 4B2B to 1.77-angstrom resolution. The active site was identified and contains a cluster of 2 metal atoms. Xu et al. (2000) concluded that the structure suggests the mechanism of action and basis for specificity, and will provide a framework for structure-assisted drug design for members of the phosphodiesterase family.
Milatovich et al. (1994) mapped the PDE4B gene to human 1p31 by a combination of Southern analysis of somatic cell hybrid lines and fluorescence in situ hybridization (FISH); they assigned the mouse homolog to chromosome 4 by Southern analysis of recombinant inbred (RI) mouse strains. Through the use of somatic cell hybrids segregating either human or rat chromosomes, Szpirer et al. (1995) mapped the PDE4B gene to human chromosome 1 and rat chromosome 5.
Bolger, G., Michaeli, T., Martins, T., St. John, T., Steiner, B., Rodgers, L., Riggs, M., Wigler, M., Ferguson, K. A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Molec. Cell. Biol. 13: 6558-6571, 1993. [PubMed: 8413254] [Full Text: https://doi.org/10.1128/mcb.13.10.6558-6571.1993]
Huston, E., Lumb, S., Russell, A., Catterall, C., Ross, A. H., Steele, M. R., Bolger, G. B., Perry, M. J., Owens, R. J., Houslay, M. D. Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase, HSPDE4B3. Biochem. J. 328: 549-558, 1997. [PubMed: 9371714] [Full Text: https://doi.org/10.1042/bj3280549]
Livi, G. P., Kmetz, P., McHale, M. M., Cieslinski, L. B., Sathe, G. M., Taylor, D. P., Davis, R. L., Torphy, T. J., Balcarek, J. M. Cloning and expression of cDNA for a human low-K(m), rolipram-sensitive cyclic AMP phosphodiesterase. Molec. Cell. Biol. 10: 2678-2686, 1990. [PubMed: 2160582] [Full Text: https://doi.org/10.1128/mcb.10.6.2678-2686.1990]
Milatovich, A., Bolger, G., Michaeli, T., Francke, U. Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse. Somat. Cell Molec. Genet. 20: 75-86, 1994. [PubMed: 8009369] [Full Text: https://doi.org/10.1007/BF02290677]
Millar, J. K., Pickard, B. S., Mackie, S., James, R., Christie, S., Buchanan, S. R., Malloy, M. P., Chubb, J. E., Huston, E., Baillie, G. S., Thomson, P. A., Hill, E. V., Brandon, N. J., Rain, J.-C., Camargo, L. M., Whiting, P. J., Houslay, M. D., Blackwood, D. H. R., Muir, W. J., Porteous, D. J. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310: 1187-1191, 2005. [PubMed: 16293762] [Full Text: https://doi.org/10.1126/science.1112915]
Obernolte, R., Bhakta, S., Alvarez, R., Bach, C., Zuppan, P., Mulkins, M., Jarnagin, K., Shelton, E. R. The cDNA of a human lymphocyte cyclic-AMP phosphodiesterase (PDE IV) reveals a multigene family. Gene 129: 239-247, 1993. [PubMed: 8392015] [Full Text: https://doi.org/10.1016/0378-1119(93)90274-7]
Szpirer, C., Szpirer, J., Riviere, M., Swinnen, J., Vicini, E., Conti, M. Chromosomal localization of the human and rat genes (PDE4D and PDE4B) encoding the cAMP-specific phosphodiesterases 3 and 4. Cytogenet. Cell Genet. 69: 11-14, 1995. [PubMed: 7835077] [Full Text: https://doi.org/10.1159/000133927]
Xu, R. X., Hassell, A. M., Vanderwall, D., Lambert, M. H., Holmes, W. D., Luther, M. A., Rocque, W. J., Milburn, M. V., Zhao, Y., Ke, H., Nolte, R. T. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science 288: 1822-1825, 2000. [PubMed: 10846163] [Full Text: https://doi.org/10.1126/science.288.5472.1822]