Journal Article Review Research Support, N.I.H., Intramural Epublish
PubMed: 40214475 DOI: 10.3390/cells14070522
Diverse Roles of the Multiple Phosphodiesterases in the Regulation of Cyclic Nucleotide Signaling in .
Cells 14(7)
Authors: Pundrik Jaiswal, Alan R Kimmel
Affiliations
- Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, MD 20892, USA.
Abstract
is a unique model used to study the complex and interactive cyclic nucleotide signaling pathways that regulate multicellular development. grow as individual single cells, but in the absence of nutrients, they initiate a multicellular developmental program. Central to this is secreted cAMP, a primary GPCR-response signal. Activated cAMP receptors at the cell surface direct a number of downstream signaling pathways, including synthesis of the intracellular second messengers cAMP and cGMP. These, in turn, activate a series of downstream targets that direct chemotaxis within extracellular cAMP gradients, multicellular aggregation, and, ultimately, cell-specific gene expression, morphogenesis, and cytodifferentiation. Extracellular cAMP and intracellular cAMP and cGMP exhibit rapid fluctuations in concentrations and are, thus, subject to exquisite regulation by both synthesis and degradation. The genome encodes seven phosphodiesterases (PDEs) that degrade cyclic nucleotides to nucleotide 5'-monophosphates. Each PDE has a distinct structure, substrate specificity, regulatory input, cellular localization, and developmentally regulated expression pattern. The intra- or extra-cellular localizations and enzymatic specificities for cAMP or cGMP are essential for degradative precision at different developmental stages. We discuss the diverse PDEs, the nucleotide cyclases, and the target proteins for cAMP and cGMP in . We further outline the major molecular, cellular, and developmental events regulated by cyclic nucleotide signaling, with emphasis on the input of each PDE and consequence of loss-of-function mutations. Finally, we relate the structures and functions of the PDEs with those of humans and in the context of potential therapeutic understandings.
MeSH
Cells, Genes, Adenylyl Cyclases, Phosphoric Diester Hydrolases, Nucleotides, Cyclic