The Multienzyme PDE4 Cyclic Adenosine Monophosphate–Specific Phosphodiesterase Family: Intracellular Targeting, Regulation, and Selective Inhibition by Compounds Exerting Anti-inflammatory and Antidepressant Actions

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Introduction

cAMP is a second messenger that is found ubiquitously in mammalian cells. It serves to transduce the action of a wide variety of hormones and neurotransmitters and can modulate signal transduction processes regulated by a range of growth factors, cytokines, and other agents. cAMP can exert acute effects on metabolic processes, muscle contraction, exocytosis, platelet aggregation, and neurotransmission, for example, as well as have long-term effects on key processes such as cell growth, differentiation, and long-term potentiation. These actions are all mediated by protein kinase A (PKA) activity, which serves to phosphorylate key target proteins and thus alter their functioning (Scott, 1991). The chain of events that allow for cAMP signaling is supplied by an extremely complex range of proteins (Houslay and Milligan, 1997). Thus, the very wide range of seven transmembrane domain (7TM) receptors (Houslay, 1992), which are capable of interacting with the guanine nucleotide regulatory protein Gs allows this G protein to bind guanosine triphosphate (GTP) and dissociate, whereupon the GTP-bound α-Gs subunit serves to stimulate the transmembrane enzyme adenylate cyclase, which then produces cAMP at the cytosolic surface of the plasma membrane (Birnbaumer et al., 1990). In addition, a number of receptors are able to inhibit adenylate cyclase activity by interacting with the inhibitory guanine nucleotide regulatory protein Gi (Houslay, 1991).

The way in which these receptor-activated G proteins are able to alter cAMP signaling is determined by the properties of the particular isoform(s) of adenylate cyclase that are expressed in a particular cell type (Houslay and Milligan, 1997). To date, at least nine forms of adenylate cyclase have been recognized (Sunahara et al., 1996). This diversity of adenylate cyclase isoforms allows for (1) differential controls on cAMP synthesis through the definition of specific “cross-talk” modulation via other signal transduction processes, (2) the localization of adenylate cyclase expression to distinct lateral domains of the cell surface plasma membrane, and also (3) distinct basal activities, which allow, in concert with the regulation of cAMP removal, distinctive cell-specific patterns of the metabolic cycling of cAMP (Houslay and Milligan, 1997).

Detection of intracellular cAMP and the generation of an intracellular response are determined through the sole action of PKA (Scott, 1991). This is a heterodimeric protein consisting of both regulatory (R) and catalytic (C) units. The binding of cAMP to the regulatory subunits causes dissociation of the complex and the release of free, activated catalytic units. However, multiple forms of both the regulatory and catalytic subunits exist. One particularly distinct feature of this is that while the R-I subunits are predominantly found in the cytosol, the R-II subunits are essentially found in the particulate fraction due to their interaction with members of a family of anchoring proteins (AKAPs). This affords the cell-type-specific spatial localization of PKA to specific intracellular sites (Faux and Scott, 1996a, Faux and Scott, 1996b, Klauck and Scott, 1995, Rubin, 1994).

Thus, both the generation and detection of cAMP occur through a large family of proteins with distinct intracellular locations and, in the case of adenylate cyclase, distinct functional-regulatory properties (Houslay and Milligan, 1997). This creates the possibility of a wide range of distinct intracellular scenarios in which cAMP production and detection are highly vectorial processes that possess distinctive regulatory features (Houslay and Milligan, 1997). Thus, anchored PKA-RII forms may serve to “sample” the [cAMP] found in distinct intracellular compartments. The localized source of cAMP generation coupled with the action of phosphodiesterases (PDEs) will serve to generate distinct compartments. The control of these may be influenced by anchored PDE4 isoforms. Thus, receptors coupled to spatially distinct adenylate cyclase isoforms in cells can be expected to elicit distinct responses by activation of particular localized PKA-II populations, with such compartmentalized responses being inherently dependent on the activity of distinct PDE isoforms.

cAMP PDE enzymes, which provide the sole means of degrading cAMP in cells, provide a complementary system of considerable complexity. Activity is supplied by a large multienzyme family, having distinct regulatory properties and intracellular location, and with particular isoforms being expressed in a cell-specific fashion (Beavo, 1995, Beavo et al., 1994, Conti et al., 1991, Conti et al., 1995b, Manganiello et al., 1995a, Manganiello et al., 1995b, Thompson, 1991, Torphy et al., 1993a). As such, the control of the degradation of cAMP through PDE activity can be considered an equal partner to the control of G protein-stimulated adenylate cyclase in determining effects on cellular functioning through the cAMP signaling pathway.

cAMP PDEs convert 3′,5′-cAMP to 5′-AMP. This activity is supplied by a multigene family (Beavo, 1995, Beavo et al., 1994, Conti et al., 1991, Conti et al., 1995b, Manganiello et al., 1995a, Manganiello et al., 1995b, Thompson, 1991, Torphy et al., 1993a). PDE1 enzymes can hydrolyze both cAMP and cGMP, with their activities being stimulated by Ca2+/CaM at physiological concentrations. Three genes (A,B,C) encode PDE1 enzymes, with additional complexity generated by alternative mRNA splicing. PDE2 enzymes similarly hydrolyze both cAMP and cGMP, but their catalytic activity can be stimulated through the binding of cGMP to a regulatory site found towards the N-terminal region of members of this isozyme family. Such stimulation occurs in a positive, homotropic (cooperative) fashion. Thus, PDE1 and PDE2 isoforms set precedents for the ability of N-terminal regions to act as regulatory domains capable of modulating catalytic activity (Vmax). This presumably occurs through conformational changes occurring in the regulatory region being transmitted through the protein to trigger a change in the catalytic unit, a region that shows strong homology between all PDE isozymes. While low cGMP concentrations can potentiate cAMP hydrolysis by PDE2 isozymes, the activity of all members of the PDE3 family, for which there are two genes (A,B), is potently inhibited by low cGMP concentrations. However, distinct from PDE2 isozymes, the PDE3 isozymes specifically hydrolyze cAMP and not cGMP, which simply serves as a competitive inhibitor, binding only to the catalytic site of PDE3 forms. Indeed, the catalytic region of the PDE3 isozyme family is characterized by a unique insert, which may be responsible for the unique properties associated with this enzyme family. Thus, regulation of cAMP levels can be either positively or negatively coupled to changes in cGMP levels through the selective expression of either PDE2 or PDE3 isozymes. This coupling may be of particular importance in cells where cGMP levels are functionally regulated. Important examples of this might include cells expressing atrial natriuretic peptide-stimulated membrane guanylate cyclase and also nitric oxide (NO)-stimulated cytosolic guanylate cyclase in smooth muscle cells, where activation can occur through NO generated in the vasculature.

Two other cAMP-specific PDE families have been described: the PDE4 (Bolger, 1994, Conti et al., 1995b) and PDE7 families (Michaeli et al., 1993). Separate genes encode each of these very distinct species.

Human PDE7 was cloned from a glioblastoma-derived cell line by functional complementation of PDE-deficient yeast (Michaeli et al., 1993). PDE7 activity is insensitive to inhibition by the type 4 selective inhibitors rolipram and Ro 201724. Use of antibodies and reverse transcription polymerase chain reaction (RT-PCR) following the initial cloning of PDE7 identified this enzyme as a previously detected novel cAMP PDE activity in T-lymphocyte cell lines (Bloom and Beavo, 1996, Ichimura and Kase, 1993). RT-PCR has been used to show expression of a PDE7 transcript in CD4/ CD 8 T lymphocytes isolated from the peripheral blood mononuclear cells of healthy individuals (Giembycz et al., 1996). In addition to being insensitive to PDE4-specific inhibitors, PDE7 is insensitive to inhibition by 3-isobutyl-1-methylxanthine (IBMX), a compound that has been shown to inhibit all other PDE families. Interestingly, although the PDE7 acronym was adopted subsequent to the molecular cloning of an IBMX-insensitive PDE (Michaeli et al., 1993), the existence of such a defined IBMX-insensitive, cAMP-specific species had been recognized sometime earlier when such an IBMX-insensitive species was resolved as a PDE form distinct from both hepatocyte and liver preparations (Lavan et al., 1989). A further difference appears that PDE7, again unlike other PDEs, may be insensitive to stimulation by Mg2+ (Lavan et al., 1989).

This chapter focuses on the cAMP-specific PDE4 isozyme family. It is these enzymes that show highest similarity in primary sequence to the Drosophila melanogaster dunce PDE, whose inactivation leads to learning defects (Dauwalder and Davis, 1995, Davis, 1988, Davis and Davidson, 1986, Nighorn et al., 1991, Qiu et al., 1991). Interest first focused on these enzymes with the discovery that they could be potently and selectively inhibited by rolipram (Nemoz et al., 1985, Reeves et al., 1987), a compound that appears to exert antidepressant effects in humans. The generation of a host of other PDE4-selective inhibitors (see e.g., Palfreyman, 1995, Souness and Rao, 1997), together with further analysis of the pharmacological properties of rolipram, led to extremely strong indications that PDE4-selective inhibitors may be of use in a wide range of major disease areas (Table I), with anti-inflammatory and anti-asthma potential being of particular note (Ashton et al., 1994, Lowe and Cheng, 1992, Masamune et al., 1995, Muller et al., 1996, Raeburn and Karlsson, 1993, Souness and Rao, 1997, Torphy, 1987, Torphy, 1994, Torphy et al., 1994, Torphy et al., 1993a, Torphy et al., 1993b, Torphy et al., 1993c, Torphy and Undem, 1991). However, alongside the proliferation of PDE4-selective inhibitors has run the discovery of an increasing number of PDE4 isoforms themselves, such that it seems likely that over 20 PDE4 isoforms will be found in humans (Bolger, 1994, Conti et al., 1995b). Such isoforms appear to be expressed in a cell-specific pattern, with expression being regulated by an array of promoters. Nevertheless, the solution of the underlying molecular and cellular mechanisms that account for this seemingly distressing complexity is likely to allow for the design of highly selective novel therapeutic agents that focus their actions on particular PDE4 isoforms, and even at particular isoforms expressed in specific cell types.

Before the advent of molecular techniques, cellular PDE activity was classified in a variety of different and potentially confusing ways. These included the general classification of “soluble” and “particulate” enzymes together with “high” and “low” Km enzymes as well as more focused descriptions of Ca2+/CaM-activated activity and cGMP-regulated activity attributed to forms with defined cAMP/cGMP substrate specificity. To determine if these various activities represented the activity of separate proteins, efforts were made to purify specific proteins and to determine their properties. In attempting this it was realized that a simple and quick way of achieving a reasonable degree of resolution was through DEAE ion exchange chromatography. This led to the original classification system, which was based on order of elution from DEAE columns, with the first eluted species being a Ca2+/CaM-stimulated enzyme, thus called type I; cGMP-stimulated as type II; the cGMP-inhibited PDE as type III; and rolipram-inhibited PDE as type IV. This, however, led to anomalies that became more apparent with the use of FPLC, as, for example, the rolipram-inhibited activity could be resolved into more than one peak, and the first peak could be resolved into both Ca2+/CAM (PDE1) and IBMX-insensitive (PDE7) forms (Lavan et al., 1989). Such a “diagnostic” system has thus now been abandoned, and naming is based on gene families monitored through a nomenclature committee (Beavo et al., 1994). This provides for a rigorous assessment of family identity based on primary sequence similarities. It is thus strongly recommended, therefore, that the “PDE1, 2, … ” nomenclature be used and not “type I, II, III,” and so on.

Over this period, however, there was considerable discussion on whether these various PDE activities did indeed reflect true isozymes or whether a single core PDE protein could be modified to alter its regulatory properties. Certainly, the acute sensitivity of PDEs to proteolysis, which has been shown to cause changes in their regulatory properties and activity as well as sensitivity to selective inhibitors (see e.g., Price et al., 1987), did nothing to aid the resolution of such issues. However, two distinct experimental approaches that developed at the same time provided excellent evidence to support the notion that distinct proteins contributed these various activities. One of these involved the generation of distinct iodinated tryptic peptide maps of purified PDEs showing sufficient similarity to indicate relatedness, presumably due to peptides emanating from the “core catalytic” unit, as well as various dissimilar peptides originating from unique regions (Takemoto et al., 1982). A complementary approach (Mumby et al., 1982) involved the generation of antisera that were able to recognize different PDE types in a species-specific fashion, thus identifying various PDE forms as immunologically distinct proteins. Such experiments provided strong support for the notion that PDE activity was supplied by a large family of isoenzymes.

The naming of the type IV PDE (PDE4) enzyme family came from studies done on the ion-exchange chromatographic separation of PDE activities from heart (Reeves et al., 1987). In that study, a fourth peak of PDE activity was resolved as eluting after the cGMP-inhibited PDE3 activity. This activity was shown to be specific for cAMP and to be uniquely sensitive to inhibition by rolipram. Subsequently, this was confirmed and elaborated on in many laboratories. The attraction of this study, in which the type IV name was coined, was undoubtedly based on the fact that it was now relatively easy to define a rolipram-inhibited, cAMP-specific PDE activity and then to generate a host of inhibitors with similar isozyme selectivity. Nevertheless, in retrospect, it is clear that this was not the original identification of a cAMP-specific PDE4 enzyme. Indeed, considering the extraordinary difficulty in being able to purify PDEs from native sources, due to their low abundance and susceptibility to degradation, it is most intriguing that a PDE enzyme that had been characterized and purified to apparent homogeneity much earlier to this (Marchmont et al., 1981, Marchmont and Houslay, 1980b) was shown to be a cAMP-specific enzyme with the characteristics expected of PDE4 enzymes, namely being cAMP specific, insensitive to calcium and low [cGMP], and, crucially, potently inhibited by the selective inhibitors Ro 172074 and rolipram (Pyne et al., 1987a, Pyne et al., 1987b). This was the so-called peripheral plasma membrane (PPM) enzyme isolated from rat hepatocytes. This purified enzyme appeared to exhibit a molecular size of 52 kDa, which is rather smaller than might be expected for known PDE4 isoforms. This might have been due to proteolysis during purification or it being either a novel PDE4 isoform or a small species generated by initiation at a downstream methionine of an established isoform. Certainly the protein-aceous material purified to apparent homogeneity in this study did contain a cAMP-PDE, as iodinated tryptic peptide maps of this material showed homology with various other purified PDEs (Takemoto et al., 1982). Thus, a rolipram-inhibited, cAMP-specific PDE4 species (Houslay and Kilgour, 1990, Marchmont et al., 1981, Marchmont and Houslay, 1980b, Pyne et al., 1987a) was undoubtedly identified and characterized some 7 years before the type IV (PDE4) acronym was coined (Reeves et al., 1987). Interestingly, another cAMP-specific PDE was also analyzed and partially purified before the type IV name was coined; this was the cAMP-specific enzyme from dog kidney (Thompson et al., 1979). However, no inhibitor studies were done on this enzyme, and it is unclear whether it was a PDE4 or a PDE7 form.

The pharmacological and biochemical resolution of the PDE4 family was then given real substance by the molecular cloning of RD1, a rolipram-inhibited, cAMP-specific PDE from rat brain (Davis et al., 1989). This was achieved by screening a rat brain cDNA library with a probe generated from the cAMP-specific Drosophila dunce PDE. Intriguingly, however, while the Drosophila dunce PDE acts as a paradigm for the mammalian PDE4 enzyme family, the dunce PDE was not inhibited by rolipram (Henkel-Tigges and Davies, 1990). This unusual feature may be due to its particular kinetic properties (Huston et al., 1996) or to sequence differences, as even single residue changes in mammalian PDE4 enzymes have been shown to lead to loss of rolipram inhibition (Pillai et al., 1993). The next leaps in our understanding were the cloning of subsequent rodent PDE4 isoforms (Swinnen et al., 1989) and the realization that it was likely that four genes encoded PDE4 activity, with additional complexity occurring through alternative mRNA splicing and the use of multiple promotors. The notion of a four-gene PDE4 enzyme family then gained a firm basis by the demonstration of an analogous multiplicity for human PDE4 isoforms (Bolger et al., 1993), the mapping of their genes to distinct chromosomes (Horton et al., 1995a, Horton et al., 1995b, Milatovich et al., 1994, Szpirer et al., 1995), and the selective occurrence of isoforms and their transcripts in different cell types and brain regions (Bolger et al., 1994, Bolger et al., 1996, Engels et al., 1995a, Lobban et al., 1994, McPhee et al., 1995, Shakur et al., 1995).

Section snippets

PDE4 Isoenzymes: A Multigene Family Enhanced by Alternative Splicing

One of the most obvious aspects of the cAMP-specific PDE4 enzymes is that they form an extremely large and diverse family of enzymes. To date, at least 13 different PDE4 enzymes have been isolated from both humans and rodents. It is likely that many more PDE4 enzymes will be isolated in the future. This diversity of enzyme forms is generated by two different mechanisms: gene duplication and alternative mRNA splicing. A description of the dunce gene of D. melanogaster (Davis and Davidson, 1986,

Mammalian PDE4 Gene Family

The cAMP-specific PDEs are encoded by four genes in mammals: PDE4A, PDE4B, PDE4C, and PDE4D. This was first demonstrated in rats (Colicelli et al., 1989, Davis et al., 1989, Swinnen et al., 1989) and later in humans (Baecker et al., 1994, Bolger et al., 1993, Engels et al., 1995b, Horton et al., 1995b, Livi et al., 1990, McLaughlin et al., 1993, Sullivan et al., 1994) and mice (Milatovich et al., 1994). The four human and four rat genes show a one-to-one correspondence, in that each of the four

Properties of PDE4 Isoforms

A fundamental question that is applicable to many signaling systems, including that of cAMP, concerns the reason for the occurrence of multiple forms of the protein species involved in performing certain steps in the pathway. The synthesis of cAMP is regulated by not only a diverse range of receptors, the reason for which is fairly obvious, but also multiple forms of adenylate cyclase and PKA (Houslay and Milligan, 1997). Multiplicity is also evident for the PKC family, ras and raf,

Methods for Defining Which PDE4 Isoenzymes Are Expressed Natively in Specific Cell Types

One key problem in undertaking such studies is the whole question of detection of native PDE isoforms. The range of splice variants is already quite daunting, and it is undoubtedly incomplete. This is not aided by the inherent difficulty in defining species by immunodetection because of the aberrant migration of most PDE4 isoenzymes on SDS-PAGE. The sizes determined from such analyses are invariably much higher than those that can be predicted from primary sequence data. Additionally, the low

PDE4 Activity in Disease States

The resolution of PDE4 isoenzymes and the fine mapping of PDE4 genes should allow the determination of alterations in PDE4 regulation and their functioning in disease states. It is possible, for example, that in certain thyroid and pituitary tumors, where activating mutations in the stimulatory G protein Gs coupled to adenylate cyclase drive proliferation (Landis et al., 1989, Lyons et al., 1990), mutations leading to aberrantly low PDE activity might also contribute to enhanced proliferation.

Pharmacological Properties of Selective PDE4 Inhibitors: Potential Clinical Roles

Much of the interest in the PDE4 genes and proteins has been stimulated by the hope that inhibitors of these enzymes would be useful in the treatment of human disease. Because of the widespread distribution of PDE4s in human tissues, a large number of disease states have been suggested as potential candidates for PDE4 inhibitor therapy (see Table I). Additionally, the isolation of a large number of different PDE4 isoforms, many with highly tissue-specific patterns of expression, has opened the

Conclusions

The development and application of PDE4-selective inhibitors unequivocally demonstrate their potential for use in a wide range of therapeutic areas. However, despite the tantalizing attractiveness of such compounds as novel therapeutic agents, more recently it has become clear that moving these compounds into the marketplace is not going to be a simple issue. A central problem relates to side effects, such as emesis, and the possibility of untoward toxicology. However, the present generation of

Acknowledgments

MDH is supported by grants from the Medical Research Council of the United Kingdom and the Wellcome Trust. GBB was supported by grants from the Department of Veterans Affairs and the National Cancer Institute, USA, as well as the NCI-supported core facilities of the Huntsman Cancer Institute. We thank Drs. T. J. Torphy, R. J. Owen, M. Perry, J. Souness, K. Jarnagin, E. R. Shelton, and M. MacLean for allowing us access to manuscripts prior to their publication. We apologize to those

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