ReveiwRegulation of cAMP and cGMP signaling: new phosphodiesterases and new functions
Introduction
Given that cyclic nucleotide signaling regulates a wide variety of cellular functions, it is not surprising that cyclic nucleotide phosphodiesterases (PDEs) are represented by a large superfamily of enzymes. From comparative, structural and functional studies, PDEs are now known to possess a modular architecture, with a conserved catalytic domain proximal to the carboxyl terminus and regulatory domains or motifs often near the amino terminus (see Figure 1). The PDE superfamily currently includes 19 different genes subgrouped into 10 different PDE families, and it is likely that more will be added in the coming years. Each family is distinguished functionally by its unique combination of enzymatic characteristics and pharmacological inhibitory profiles. Individual PDE families also exhibit regulation by distinct allosteric activators or inhibitors. Finally, each gene within a family also has specific tissue, cellular, and sometimes also subcellular distributions. Thus the precise cellular and subcellular profile of PDE expression determines how a tissue responds to first messengers. Here, we review recent work on the newly discovered PDE families (PDE8, PDE9 and PDE10) and also recent insights into the roles of other specific PDEs in the regulation of T-cell activation, insulin secretion, growth, fertility and penile erection.
Section snippets
New PDEs
The past year has provided a number of surprises in the cyclic nucleotide signaling field. Not only was a new cAMP target discovered 1••, 2••, but also three new phosphodiesterase families, PDE8, PDE9 and PDE10 were identified, essentially simultaneously, by several independent laboratories 3•, 4•, 5, 6•, 7•, 8•, 9•, 10•, 11•.
PDE8A and PDE8B
PDE8A is specific for the hydrolysis of cAMP, with a low KM of approximately 70 nM 3•, 4•. Interestingly, PDE8 was the first example (PDE9 is now the second) of a PDE that is not inhibited effectively by the non-selective inhibitor, IBMX. Thus it should be emphasized that the lack of an effect of IBMX may not be a useful indicator that PDEs do not regulate a physiological function in all cases. In mouse, PDE8A expression is highest in testis followed by eye, liver, kidney, skeletal muscle,
PDE9A
Unlike PDE8, PDE9 is specific for the high-affinity hydrolysis of cGMP, with a KM of 0.07 μM 6•, 7•. Like PDE8, however, PDE9 is not effectively inhibited by IBMX. PDE9 is expressed in small intestinal smooth muscle (SH Soderling, JA Beavo, unpublished data), kidney, liver, lung, brain, testis, skeletal muscle, heart, thymus and spleen 6•, 7•. To date, four 5′ alternative splice variants have been identified for PDE9; however, the functional consequence of these variants are currently unknown [8
PDE10A
PDE10, the most recently described phosphodiesterase, was reported simultaneously by three independent groups 9•, 10•, 11•. PDE10 has the capacity to hydrolyze both cAMP and cGMP; however, the Km for cAMP is approximately 0.05 μM, whereas the KM for cGMP is 3 μM. In addition, the Vmax for cAMP hydrolysis is fivefold lower than for cGMP. Because of these kinetics, cGMP hydrolysis by PDE10 is potently inhibited by cAMP in vitro, suggesting that PDE10 may function as a cAMP-inhibited cGMP
New functions for ‘old’ PDEs
The past two years have seen an explosion in our understanding of the physiological functions that phosphodiesterases regulate. One of the more satisfying aspects of these studies is that they have borne out the prevailing premise that distinct phosphodiesterases regulate specific cellular functions. We will describe several recent examples.
Conclusions
We have highlighted recent progress in the phosphodiesterase field related to the identification of previously unknown PDEs (see http://depts.washington.edu/pde/ for current PDE nomenclature updates), and to the characterization of some of the cellular functions that PDEs regulate. There has not been room to discuss other important studies in this burgeoning field, including PDE subcellular targeting (I Verde et al., unpublished data; 35, 36••, 37•) and PDE regulation 38•, 39•. The past 18
Update
After submission of this manuscript the first report of a new PDE11 gene family was published [41••]. This isozyme hydrolyzes both cAMP and cGMP and contains a GAF domain. Little is yet known about its regulation.
Acknowledgements
The authors would like to thank Elinor T Adman of the Department of Biological Structure at the University of Washington for her help in analyzing the PAS domain structure of PDEB. Work from the authors was supported by grants DK2173, HL60178 and HL4498 from the National Institutes of Health.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (41)
- et al.
A family of cAMP-binding proteins that directly activate Rap1
Science
(1998) - et al.
Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP
Nature
(1998) - et al.
Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase
Proc Natl Acad Sci USA
(1998) - et al.
Isolation and characterization of PDE8A, a novel human cAMP-specific phosphodiesterase
Biochem Biophys Res Commun
(1998) - et al.
Molecular cloning and characterization of human PDE8B, a novel thyroid-specific isozyme of 3′,5′-cyclic nucleotide phosphodiesterase
Biochem Biophys Res Commun
(1998) - et al.
Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase
J Biol Chem
(1998) - et al.
Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases
J Biol Chem
(1998) - et al.
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
(1998) - et al.
Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)
J Biol Chem
(1999) - et al.
Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclic nucleotide phosphodiesterase
Gene
(1999)
Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A
Proc Natl Acad Sci USA
White collar 2, a partner in blue-light signal transduction, controlling expression of light-regulated genes in Neurospora crassa
EMBO J
PAS is a dimerization domain common to Drosophila period and several transcription factors
Nature
Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL
Science
Identification of functional domains of the aryl hydrocarbon receptor
J Biol Chem
PIF3, a phytochrome-interacting factor necessary for normal photoinduced signal transduction, is a novel basic helix–loop–helix protein
Cell
Structure of a biological oxygen sensor: a new mechanism for heme-driven signal transduction
Proc Natl Acad Sci USA
1.4 A structure of photoactive yellow protein, a cytosolic photoreceptor: unusual fold, active site, and chromophore
Biochemistry
Biological sensors: more than one way to sense oxygen
Curr Biol
The GAF domain: an evolutionary link between diverse phototransducing proteins
Trends Biochem Sci
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