Cyclic Nucleotide Phosphodiesterases
Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and/or cGMP. They function in conjunction with adenylyl and guanylyl cyclases to regulate the amplitude and duration of cell signaling mechanisms mediated via cAMP and cGMP. They therefore serve to regulate a range of biological responses to first messengers such as light, hormones, neurotransmitters and odorants. Two classes of functional PDEs (which do not share any sequence homology) are recognized: Class II PDEs have to date only been found in lower eukaryotes and are not as well characterized as Class I PDEs. Class I PDEs are found in all eukaryotic cells, either in the cytoplasm or bound to intracellular organelles or membranes. They all contain an approximately 250 amino acid catalytic domain near the C-terminus that is conserved across families within this class. This overview focuses on the Class I PDEs identified in mammalian cells.
Sequence analyses suggest that there are at least 11 different families of mammalian PDEs, most of which contain more than one gene product. Furthermore, many of these genes can be alternately spliced in a tissue specific manner to give several different mRNAs/proteins with altered regulatory properties or subcellular localization. PDEs are named to precisely identify the isozyme being referenced. For example, MMPDE4A1 refers to the Mus musculus PDE4 family, gene A, splice variant 1.
Each PDE family, and even PDEs within a family, can display different substrate specificities, kinetics, allosteric regulation and subcellular localization. Therefore, the expression profile of PDEs within a given cell will determine which PDEs regulate cyclic nucleotide levels in that cell or subcellular region. The distinct cellular localization and biophysical characteristics of the various PDEs suggest that individual PDEs are individually regulated and play distinct roles in specific physiological processes. For example, the three gene products of the PDE1 family are activated by calcium/calmodulin and are probably inactivated by phosphorylation by protein kinase A and/or calmodulin (CaM) kinase II. They are thought to participate in the feed-forward amplification of neuronal signals. Similarly, PDE2A has been shown to play a role in regulating aldosterone production in adrenal glomerulosa cells through integration of cAMP and cGMP signals. PDE3s, the cGMP-inhibited PDEs, allow cGMP to potentiate a cAMP signal in cells where they are expressed. PDE3A is involved in regulation of platelet aggregation by cGMP, while PDE3B mediates insulin regulation of lipolysis in adipocytes and IGF-1 or leptin inhibition of insulin secretion in pancreatic beta cells. PDE4s (4A, 4B, 4C and 4D) are widely expressed and are likely responsible for modulating a variety of functions, including emesis, lymphocyte-mediated inflammation and follicle stimulating hormone responsiveness in Sertoli cells. PDE5A plays a role in regulating smooth muscle tension in humans, and sildenafil, a selective PDE5A inhibitor, is used as a therapeutic agent to treat erectile dysfunction in man. PDE6A and 6B play a central role in visual phototransduction through rapid modulation of cGMP hydrolysis. PDE7A is induced upon T-cell activation and thought to play a role in modulation of T-cell responsiveness.
The remaining PDEs have only recently been described and specific cellular functions for each isozyme have not been elucidated. Early data suggest that PDE7B may participate in signal transduction in the liver and pancreas. PDE8A is highly expressed in pre-meiotic spermatids, while PDE8B is found almost exclusively in the thyroid. PDE9A is found primarily in the kidney, whereas PDE10A is abundant in the testis and brain. PDE11A is found in skeletal muscle, as well as in the prostate. It is likely that these PDE isozymes play important roles in these tissues.
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