| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Division of Reproductive Biology Department of Gynecology and Obstetrics Stanford University School of Medicine Stanford, California 94305-5317
 |
INTRODUCTION |
|---|
 TOP INTRODUCTION MODULAR STRUCTURE OF PDEsMECHANISMS OF REGULATION OF...SIGNALING CASCADES INVOLVING...HOW PDE PHARMACOLOGY MAY...REFERENCES |
|---|
Over the years, new dimensions have added complexity to cyclic nucleotide signaling. It is now established that protein kinase As (PKAs) are not the only intracellular effectors of cAMP. Cyclic nucleotide gated channels (1) and cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs or EPACs) (2, 3) allow branching of the cyclic nucleotide signals. Compartmentalization of the different components of the signaling cascade is an important determinant of the signal outcome (4), and feedback mechanisms control practically every step of the cyclic nucleotide pathway (5). Therefore, a holistic approach to signaling may provide a better understanding of how cyclic nucleotides function in the cell. Signaling pathways, including cyclic nucleotides, are organized in a nonlinear fashion (6). When an extracellular stimulus reaches the plasma membrane, it is distributed into an array of signals that involves most transduction systems present in a cell, and each component of the signaling cascade is a node of inputs and outputs connecting different signaling pathways. Combinatorial signaling, coincidental detection, signal cross-talk, and signal channeling are buzzwords used to describe this intracellular network. In this context, some steps in the signaling cascade may have new and unexpected functions.
In the cyclic nucleotide cascade, phosphodiesterases (PDEs) are the enzymes that hydrolyze cAMP and cGMP, inactivating these second messengers. Together with phosphatases, PDEs are negative steps in the signaling pathway, and signal termination was thought to be their only function. However, they may have a much broader role in signaling when the whole intracellular network is considered. In view of the presence of multiple intracellular effectors of cyclic nucleotides, PDEs may play a role in distributing the cyclic nucleotide signal among PKAs, cyclic nucleotide-gated channels, and cAMP-GEFs. Because they are regulated by multiple second messengers and kinases, PDEs also integrate the cyclic nucleotide cascade with other signaling pathways. Finally, PDEs may contribute to signal compartmentalization by controlling the diffusion of the second messenger to different cellular compartments. Here, I will review the most recent advances concerning the structure of PDEs and their role in endocrine cell signaling, and will conclude by highlighting possible applications of the pharmacology of PDEs for the treatment of endocrine disorders.
|
MODULAR STRUCTURE OF PDEs |
|---|
|
TOPINTRODUCTIONMODULAR STRUCTURE OF PDEsMECHANISMS OF REGULATION OF...SIGNALING CASCADES INVOLVING...HOW PDE PHARMACOLOGY MAY...REFERENCES |
|---|
). Using the most widely accepted
nomenclature (13), the PDE family is indicated by an Arabic numeral,
followed by a capital letter indicating the gene within a family, and a
second Arabic numeral indicating the splicing variant derived from a
single gene (for example PDE1C3: family 1, gene C, splicing variant
3).
|
) (14). This
domain is structurally related to other metal-dependent
phosphohydrolases with conserved HD motif (15), pointing to the
important role of divalent cations in cyclic nucleotide hydrolysis
(16). In addition to the signature sequence AaxxHDxDHxG identified by
sequence comparison, a number of conserved residues have been
identified within this catalytic domain, and their mutagenesis often
impacts catalysis (14). Spontaneous mutations in PDE6 within the
catalytic domain and their association with major defects of the retina
further support the importance of this domain in the enzyme function
(17). The recent release of the crystal structure of the catalytic
domain has reconciled the many site-directed mutagenesis studies done
on this region of the PDEs (18). The PDE4 catalytic domain is a compact
structure composed of 17 
-helices divided into three subdomains,
with the most conserved residues involved in the formation of the
catalytic pocket (18). More importantly, this structural analysis has
confirmed the presence of metal ions in the catalytic pocket, and it
will certainly provide conclusive answers regarding the exact
interactions of this domain with cyclic nucleotide substrates and model
inhibitors (19).
The arrangement of domains around this catalytic core, as well as the
presence of a large number of splicing variants, points to a modular
structure of PDEs (5, 14). Several domains with a variety of proven or
putative functions have been identified at the amino terminus portion
of most PDE forms (Fig. 1) and are distinctive characteristics of each
family (14). These include protein-protein interaction domains as well
as domains that bind small molecules such as cyclic nucleotides. In
addition, phosphorylation domains that control the catalytic function
have been mapped at the amino terminus of most PDEs (reviewed in Ref.
5). Domains present at the carboxyl terminus of PDEs may be involved in
dimerization, as has been suggested for PDE4 (20) and PDE1 (21), or may
function as a regulatory domain being a target for phosphorylation
(22).
Although viewed by some as an oversimplification, it is probable that
all these different domains regulate PDE catalysis by a common
mechanism. The regulatory domains that flank the catalytic domains
function as a sensor of intracellular signals. Reception of these
signals produces a change in conformation of the PDE so that an
inhibitory domain no longer exerts a negative constraint on the
catalysis. The presence of an inhibitory domain is inferred by
biochemical studies with controlled proteolysis of PDE1, PDE2, and PDE4
and deletion mutagenesis of PDE1, PDE3, PDE4, and possibly PDE7 (5).
Moreover, the regulation of PDE6 by the inhibitory 
-subunit again
points to the important role of inhibitory constraint in PDE catalysis.
Along the same line, PDE4s have two unique modules that are conserved
in the four genes that compose this family. On the basis of their
conservation, they have been named upstream conserved region 1 and 2
(UCR1 and UCR2) (23). Functionally, the UCR2 conserved domain
corresponds to an autoinhibitory domain that negatively regulates the
catalytic activity (24), while regulatory phosphorylation sites have
been mapped in the UCR1 (25). A model for the interactions between
these regions has been developed on the basis of domain binding and
regulation of catalysis (26). While this model has been recently
confirmed by others (27), it remains to be determined to what extent it
may be applied to PDEs that belong to other families.
Significance of the PDE Complexity
Domain shuffling may explain why a large number of PDE variants
with divergent amino and carboxyl termini have been identified. As an
example, the PDE4D gene encodes five well characterized splicing
variants, a property that is inherited from Drosophila (14).
These variants are generated by alternate splicing and/or different
promoter usage (14). More importantly, these variants are subjected to
different regulations (see below) or are targeted to different
subcellular compartments. Targeting domains have been identified in
most PDEs. PDE3s have a domain that includes six transmembrane
hydrophobic helices, which target them to the endoplasmic reticulum.
This domain is absent in some soluble PDE3 splicing variants (28). Two
variants with soluble and particulate distribution have been described
for PDE2 and PDE7 (14). A domain that interacts with RACK1, a scaffold
protein that binds activated protein kinase C (PKC) isoforms, was
identified at the amino terminus of one of the five PDE4D variants
(29), and putative SH3 interacting domains have been reported for one
PDE4A and one PDE4D variant (30, 31). A scaffold protein that anchors
PDE4D to the Golgi/centrosome structures in the vicinity of PKAs has
also been reported (32, 33). Although the physiological impact of this
differential targeting is largely unknown, these findings lend support
to the idea that PDE subcellular targeting may have a role in signal
compartmentalization (34).
The divergent properties and the presence of distinct regulatory domains in PDEs explain, at least in part, the heterogeneity of the PDE superfamily. A cell utilizes PDEs with different properties and regulations to adapt to the large variety of signals to which it is exposed, to control cyclic nucleotide accumulation in different subcellular compartments, and to integrate different signaling pathways. More difficult to understand is why multiple genes are present within a family because the corresponding proteins have largely overlapping properties and regulations. Recently, it has been shown that inactivation of only one of the four PDE4 genes present in the mouse produces profound and unexpected phenotypes, suggesting that the functions of different PDE genes do not overlap (35). In addition, in situ studies on PDE mRNA expression in brain have uncovered some specificity in the expression of genes belonging to the same family. PDE4B, for instance, is expressed in the granular layer of the cerebellum, while PDE4D is expressed in the Purkinje cells (36). Thus, it is also possible that gene duplication may have occurred to increase the control of PDE expression in a tissue- and developmental-specific fashion.
|
MECHANISMS OF REGULATION OF PDEs |
|---|
|
TOPINTRODUCTIONMODULAR STRUCTURE OF PDEsMECHANISMS OF REGULATION OF...SIGNALING CASCADES INVOLVING...HOW PDE PHARMACOLOGY MAY...REFERENCES |
|---|
Protein-Protein Interaction and PDE Function
PDE1s were among the first targets for calmodulin (CaM) to be
identified, and activation of cGMP hydrolysis has been used as a CaM
bioassay for more than 20 yr. CaM binding modules, which consist of a
basic amphypatic helix, have been identified by protein homology and by
deletion mutagenesis in all proteins derived from the three PDE1 genes
(37). Several pieces of evidence indicate that the CaM binding domain
affects the catalytic domain indirectly by controlling the interaction
of an autoinhibitory domain with the catalytic domain (21). Using
deletion mutagenesis, this autoinhibitory domain has been mapped to a
region between the two CaM binding sites in PDE1A1 (37).
Ca++ and CaM produce a major increase in PDE
activity, suggesting that the enzyme may be completely inactive in the
absence of Ca++. Of interest is the fact that the
affinity for Ca++/CaM is different between the
different PDE1 proteins. The PDE1A gene encodes two splicing variants,
PDE1A1 and PDE1A2. CaM is 10 times more potent in activating A1 than
A2, indicating that splicing is a means to regulate sensitivity to
Ca++ and CaM (37). Additional data comparing
isoenzymes from brain, heart, and lung have shown differences in the
affinity of PDE1B and PDE1C for CaM (38). CaM binding is also regulated
by PDE1 phosphorylation (see below).
The role of PDEs in light perception underscores the importance of PDEs
in signaling. We are able to sense visual cues because light causes a
dramatic decrease in cGMP in the retina via activation of a PDE. In
this pathway, light-activated rhodopsin interacts with the G protein
transducin that, in turn, activates PDE6, which hydrolyzes cone and rod
cGMP (39, 40). The decrease in cGMP results in closure of cGMP-gated
channels in the membrane, thus causing hyperpolarization. The PDE6
expressed in the retina is a tetramer composed of two distinct - and
ß-subunits and two -subunits in rods, with a slightly different
2-dimer expressed in cones (41, 42). Two -subunits bind the
function as inhibitors of the cGMP hydrolytic activity of the - and
ß-subunits. In addition, a 
-subunit copurifies with PDE6 and may
play a role in the membrane association of this PDE (43). The site of
interaction of the -subunit on the ß-subunits has been
identified by several laboratories and mapped to regions surrounding
the catalytic domain (44). This interaction completely suppresses cGMP
hydrolysis. Transducin controls the interaction between - and
ß-subunits, but it is unclear whether it interacts directly with
the -subunits or with the ß-catalytic subunits.
PDE5, which is widely expressed in tissues outside the retina, has
considerable homology with PDE6. Hence, the idea has been put forward
that the activity of PDE5 may be regulated by a homolog of the
-subunit. Indeed, there are reports suggesting that
proteins immunologically related to the retina -subunit are
expressed outside the retina (45). The exact function of these novel
proteins remains to be determined. Other sensory cues may use membrane
signal transduction machinery involving G protein interaction with a
PDE, as suggested for the taste buds (46).
Cyclic Nucleotide and Other Allosteric Regulations of PDEs
The regulation of PDEs through allosteric binding of cyclic
nucleotides was discovered in the 1970s (47). PDE2 binds cGMP with an
affinity of approximately 100 nM and produces an allosteric
change in the catalytic domain. Because of this allosteric regulation,
the enzyme hydrolyzes both cAMP and cGMP with positive cooperative
kinetics. However, in the intact cell this enzyme probably functions as
a cGMP-stimulated cAMP PDE. This property allows integration of the
cGMP- and cAMP-regulated pathways, as suggested for atrial natriuretic
factor (ANF) signaling (48).
Structurally related cGMP binding domains have been identified in PDE5,
PDE6, PDE9, and PDE10 (49). In PDE5, occupancy of this site may
modulate the ability of the enzyme to be phosphorylated by protein
kinase G (50, 51). In PDE6, cGMP binding regulates the affinity of
ß-dimers for the inhibitory -subunit (52), while little is
known about the role of cGMP binding in PDE9 and PDE10. Similar domains
have been found in proteins other than PDEs and have been termed GAF
domains (cGMP-specific and cGMP-stimulated PDEs, Anabaena
adenylyl cyclase and Escherichia coli Fh1A) (53).
The presence of these domains in species where cGMP is not produced has
led to the recent proposal that the GAF domain in PDEs may not serve to
bind cGMP but is involved in interactions with other unknown small
ligands (49).
On the basis of sequence homology with a domain found in proteins from bacteria to eukariots, a PAS (Period, Arnt, Sim) domain was identified in PDE8 (54). This domain functions as a signal detector and is usually associated with a heme or a chromophore cofactor (55). In archaea, the PAS domain of FixL is a sensor for oxygen or possibly nitric oxide (56). Although the function of the PAS domain in PDE8 is not known, it may be important for protein-protein interaction or for sensing concentrations of a small ligand (49), suggesting a novel mode of regulation for PDEs.
Posttranslational Modification
There are now reports demonstrating phosphorylation of PDE1,
PDE3, PDE4, PDE5, PDE6, and possibly PDE7 (reviewed in Ref. 5). With
some rare exceptions, phosphorylation occurs on regulatory domains
present at the amino terminus of the PDE protein. Several kinases
including PKA, protein kinase B (PKB), mitogen-activated protein kinase
(MAPK), and calmodulin kinase (CaMK) catalyze these regulatory
phosphorylations (see below).
|
SIGNALING CASCADES INVOLVING PDEs IN ENDOCRINE CELLS |
|---|
|
TOPINTRODUCTIONMODULAR STRUCTURE OF PDEsMECHANISMS OF REGULATION OF...SIGNALING CASCADES INVOLVING...HOW PDE PHARMACOLOGY MAY...REFERENCES |
|---|
The PI-3 Kinase Pathway and Activation of PDE3
Insulin and IGF-I binding activates the receptor tyrosine kinase
with phosphorylation and recruitment of adapter proteins, including
insulin receptor substrate 1–4 (IRS1–4) (57). Once phosphorylated,
these adapters recruit several effectors including the lipid
phosphatidylinositol 3 kinase (PI-3K). The phosphatidyl
triphosphate lipid formed serves as an anchor and recruits to
the membrane the kinase PDK1/2 and downstream kinase PKB/AKT
(Fig. 2) (58). There is now ample
evidence that PDE3s integrate this PI-3K signaling cascade with the
cyclic nucleotide-regulated pathway. A large number of observations are
consistent with the presence of this signaling cascade in the cell.
Activation of PI-3 kinase by insulin is associated with an increase in
PDE3 activity in adipocytes, and the PDE3 activation is blocked by
wortmannin and LY 294002, both of which are inhibitors of PI-3 kinases
(59). In addition, insulin treatment causes the incorporation of
32P-phosphate in PDE3B (60, 61). That PDE3B is
directly phosphorylated by PKB is demonstrated by cell-free experiments
with recombinant proteins (62). Two possible phosphorylation sites have
been identified in PDE3B. Ser302 of rat PDE3B was identified by
phosphopeptide mapping of PDE3B from insulin-stimulated cells (63).
Conversely, site-directed mutagenesis has indicated Ser273 as the major
site of PKB phosphorylation (64). While the sequence surrounding Ser273
conforms with the consensus for PKB phosphorylation, Ser302 is an
anomalous site because it is also phosphorylated by PKA. Whether both
sites are used in a cell-specific fashion is unclear and requires
further experimentation. Recently, Rondinone et al. (65)
have proposed that an additional mechanism of PDE3 activation by
insulin may directly involve phosphorylation of PDE3B by the PI-3K
associated with the insulin receptor.
|
). The
PKA activation that follows an increase in cAMP causes activation of
HSL by phosphorylation on one or more sites (66). In adipocytes,
insulin inhibition of lipolysis is mediated by a decrease in cAMP
levels and is associated with a decreased phosphorylation of HSL. Both
in vitro and in vivo insulin effects are blocked
by specific PDE3 inhibitors (28, 67) pointing to an important role of
this PDE. Moreover, the phosphorylation and activation of PDE3B
correlates with the inactivation of PKA and the dephosphorylation of
HSL. Thus, PDE3 phosphorylation appears to be a crucial step in
mediating the effect of insulin on lipid metabolism. The
antiglycogenolytic effects of insulin may also be mediated, at least in
part, by the same pathway involving a PDE3 (68).
A similar PI-3K, PKB, and PDE3B cascade is activated by leptin (OB), a
recently discovered hormone involved in the control of fat metabolism
and food intake (69). The peripheral effects of leptin are mediated by
the activation of receptors that are structurally related to the
cytokine receptors which signal through the janus kinases. This kinase,
in turn, phosphorylates IRS-1 and IRS-2 promoting the recruitment and
activation of PI-3 kinase (Fig. 2). Similar to what has been shown for
insulin, PI-3 kinase activation causes PKB and PDE3B activation (70).
The resulting decrease in cAMP mediates the antiglycogenolytic effects
of leptin in hepatocytes.
Because IGF-I shares the same signaling pathway with insulin, IGF-I regulation of PDE3 may be important in the regulation of cell entry and exit from the cell cycle. In Xenopus eggs, a PDE with the properties of PDE3 is activated by AKT and is an important step in insulin-like growth factor (IGF)-induced resumption of meiosis (71, 72). A PDE3A is the predominant form that is also expressed in mammalian oocytes, and inhibition of this enzyme blocks the resumption of meiosis that follows the gonadotropin stimulation in vitro and in vivo (73, 74). With the same signaling cascade, IGF-I regulates insulin secretion in islet ß-cells by regulating a PDEB (75, 76). In general, it is expected that all the growth factor pathways that use PI-3K may use the PDE3 activation to regulate cAMP levels. This could provide a means to modulate the gating effects of cAMP (77) on the mitogen-activated protein (MAP) kinases signaling pathway, and to control exit and entry from the cell cycle.
PDEs as Homeostatic Regulators
Manipulation of hepatocytes with nonhydrolyzable cAMP analogs
demonstrated that a rapid feedback controlling cAMP is operating in
these cells (78). Accumulation of the cAMP analog in the cells
activates PKA, which in turn activates a PDE. The ultimate result is a
decrease in endogenous cAMP levels. With the discovery that a PDE3 is a
substrate for PKA, it was proposed that this PDE is involved in these
feedback mechanisms (79, 80). More recently, data in thyroid cells also
have shown that PDE4 is activated by hormones that increase cAMP via a
PKA-dependent mechanism (81). PKA phosphorylates PDE4D3, one of the
variants derived from the PDE4D genes, and phosphorylation is
associated with an increase in PDE activity (25, 81). The residues
phosphorylated by PKA have been mapped by site-directed mutagenesis to
the amino terminus of PDE4D3 (25). These observations have been
confirmed and extended by demonstrating that introduction of a
negatively charged amino acid in position 54 produces an activated
enzyme (82). Thus, PDE3 and PDE4 are both rapidly activated by PKA,
depending on the cell in which they are expressed (Fig. 3).
|
During the characterization of the mechanisms causing desensitization,
it was observed that an increase in cyclic nucleotides produces an
increase in PDE activity (84). This activation was thought to be a
mechanism of desensitization that cooperated with receptor/G protein
uncoupling. With the limited knowledge of PDE heterogeneity available
at that time, little was known about the PDE involved except that the
enzyme was a cAMP-specific PDE and that the regulation required protein
synthesis and PKA activation (84). A better understanding of this
second feedback mechanism has come with the cloning of the PDE4 genes.
Stimulation with hormones that increase cAMP invariably produces an
increase in PDE4 mRNA and de novo synthesis of PDE4 proteins
(85). This is most evident for the PDE4D gene. Long-term FSH
stimulation of Sertoli cells causes more than a 100-fold increase in
PDE4D mRNA, the accumulation of PDE4D1/D2 variants, and more than a
10-fold increase in PDE activity (86). Identical induction has been
observed in most cells (14), suggesting that this is a ubiquitous
feedback regulation of cAMP, thus providing a mechanistic explanation
of the early findings on long-term, cycloheximide-sensitive PDE
activation (Fig. 3).
The impact of the PDE feedback on cAMP signaling is emerging from studies on PDE4D knockout mice (35). PDE4D-null mice display a 30–40% decrease in growth rate during puberty, and the adults are usually smaller than their littermates. The decreased growth is associated with a decrease in circulating IGF-I levels, suggesting a disruption of the GH-IGF-I axis. In addition, the homozygous PDE4D-null females display reduced fertility with litter size approximately one-third of normal. This reduction in fertility is associated with a 70–80% decrease in ovulation rate compared with wild-type littermates (35). Surprisingly, when the sensitivity to gonadotropin is measured in granulosa cells from the PDE4D-null mice, a decrease in responsiveness to hCG was observed (35). This decreased response is difficult to reconcile with the common tenet that PDE inhibition leads to an increased cAMP accumulation and cAMP signaling. Pending additional experiments to clarify the exact cause of this decreased response, we propose that inactivation of the PDE4D-PKA feedback loop causes a desensitization of the cAMP signaling pathway at the level of receptor/G protein. Thus, PDE4 regulation allows appropriate cAMP signaling by protecting from desensitization. If confirmed, this concept may have important implications in human diseases as end-organ resistance may be associated with inherited PDE4 inactivating mutations.
Disruption of PDE4D expression also affects muscarinic cholinergic responses in the airway (87). Mice deficient in PDE4D do not respond to methacholine with an increase in airway resistance, in spite of a normal complement of muscarinic cholinergic receptors. This phenotype may be caused by an increase in sensitivity to noradrenaline, which causes relaxation of smooth muscle cells. Alternatively, PDEs may directly play a role in M3 muscarinic receptor signaling that mediates the contractile response of acetylcholine (87), again supporting a role for PDE4D as a homeostatic regulator of signaling.
The PDE4 feedback loop may have an important impact under those
pathological conditions in which cAMP accumulation is deregulated.
Mutations in Gs produce a constitutively
active protein that maintains adenylyl cyclase in a chronically
activated state. These mutations are responsible for the phenotype of
patients with McCune-Albright syndrome (88) and are probable causes of
a number of adenomas of the pituitary and thyroid (89). There is also
abundant literature for constitutive activation of pituitary hormone
receptors that cause chronic cAMP elevation (90). All these spontaneous
mutations cause a marked induction of PDE4 and possibly other PDEs both
in vitro (91) and in vivo (92). The PDE4
activation must have an impact on growth as the proliferative effects
of the Gs mutations are seen in
vitro only after inhibition of PDE4 (93). Therefore, it is
possible that the abnormal growth induced by
Gs or receptor mutations is modified by the
presence of different PDE alleles. Ongoing experiments will determine
whether polymorphisms or mutations of a PDE4 exist in humans.
|
HOW PDE PHARMACOLOGY MAY IMPACT ENDOCRINOLOGY |
|---|
|
TOPINTRODUCTIONMODULAR STRUCTURE OF PDEsMECHANISMS OF REGULATION OF...SIGNALING CASCADES INVOLVING...HOW PDE PHARMACOLOGY MAY...REFERENCES |
|---|
In spite of well established effects in vitro and advances in PDE pharmacology, the use of PDE inhibitors to manipulate endocrine cell responses is an unexplored field. For example, little is known about the functions of PDE8B expressed in the thyroid gland (10). Because of this restricted pattern of expression, this enzyme may be a target to specifically manipulate cAMP levels in thyrocytes and to enhance thyroid hormone production and/or to increase sensitivity of the gland to TSH stimulation.
There are two major areas where PDE inhibitors may be used to manipulate endocrine systems. They may be used for the control of hormone secretion and in the manipulation of end-organ sensitivity to hormones. Several studies have indicated that PDE inhibition may be used as an insulin secretagogue and as hypoglycemic agents. Glucose is the major regulator of insulin secretion by ß-cells of the islets of Langerhans, and its actions are potentiated by an increase in intracellular cAMP (96). In clonal insulin secreting cell lines as well as human and rat islet cell preparations, PDE3 inhibition augmented glucose-induced insulin secretion (97). In support of this concept, insulin secretagogues that were effective in vivo were found to be PDE3 and PDE4 inhibitors (98). Thus, PDE inhibition may be a viable strategy to manipulate insulin secretion and may be used in conjunction with other agonists that increase cAMP in ß-cells. Because PDE4 inhibitors have antiinflammatory effects, the inflammatory component of type 1 diabetes may be ameliorated by PDE inhibition, as has been shown in the NOD mouse model (99).
Pituitary hormone secretion may be another possible site of PDE manipulation. The hypothalamic pituitary adrenal axis is very sensitive to the PDE4 inhibitor dembuphyllin (100, 101). Given orally or intraperitoneally, a marked rise in serum corticosterone follows administration of this inhibitor. LH release is also stimulated by these inhibitors, suggesting that this may be a strategy to manipulate pituitary secretion in vivo.
In view of their marked synergism with hormones that signal through cAMP, PDE inhibitors may be used to augment hormonal stimulation. The power of this approach is underscored by data obtained in the ovarian follicle. Treatment of these follicles with a PDE4 inhibitor causes oocyte maturation and ovulation, mimicking the LH effects (72). It should then be possible to use these inhibitors to potentiate the effect of gonadotropins in the ovary. Conversely, PDE3 inhibitors have been shown to block oocyte maturation without affecting granulosa cells, providing a paradigm for novel contraceptive strategies (72, 73).
In conclusion, we believe that manipulation of PDE activity in endocrine cells may have considerable therapeutic potential. Once the repertoire of PDE expressed in endocrine cells is established, it should not be long before new generations of selective PDE inhibitors are used to manipulate endocrine cell responses and hormone secretion.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
Work in the author’s laboratory is supported by NICHD Grants HD-20788, HD-31544, and the U54 Center grant HD-31398
Received for publication May 2, 2000. Accepted for publication June 29, 2000.
|
REFERENCES |
|---|
|
TOPINTRODUCTIONMODULAR STRUCTURE OF PDEsMECHANISMS OF REGULATION OF...SIGNALING CASCADES INVOLVING...HOW PDE PHARMACOLOGY MAY...REFERENCES |
|---|
-subunits. Proc Natl Acad Sci USA 93:5407–5412 and subunits.
J Biol Chem 274:18813–18820 Mol Endocrinol 9:1279–1287. Biochem Biophys Res Commun 168:1184–1193[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  M. Zhang, H. Ouyang, and G. Xia The signal pathway of gonadotrophins-induced mammalian oocyte meiotic resumption Mol. Hum. Reprod., July 1, 2009; 15(7): 399 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Andric, M. M. Janjic, N. J. Stojkov, and T. S. Kostic Protein kinase G-mediated stimulation of basal Leydig cell steroidogenesis Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1399 - E1408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Cazabat, R. Libe, K. Perlemoine, F. Rene-Corail, N. Burnichon, A.-P. Gimenez-Roqueplo, L. Dupasquier-Fediaevsky, X. Bertagna, E. Clauser, P. Chanson, et al. Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas Eur. J. Endocrinol., July 1, 2007; 157(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zaccolo and M. A. Movsesian cAMP and cGMP Signaling Cross-Talk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology Circ. Res., June 8, 2007; 100(11): 1569 - 1578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hatae, N. Aksentijevich, H. W. Zemkova, K. Kretschmannova, M. Tomic, and S. S. Stojilkovic Cloning and Functional Identification of Novel Endothelin Receptor Type A Isoforms in Pituitary Mol. Endocrinol., May 1, 2007; 21(5): 1192 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Levallet, J. Levallet, H. Bouraima-Lelong, and P.-J. Bonnamy Expression of the cAMP-Phosphodiesterase PDE4D Isoforms and Age-Related Changes in Follicle-Stimulating Hormone-Stimulated PDE4 Activities in Immature Rat Sertoli Cells Biol Reprod, May 1, 2007; 76(5): 794 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Murray, H. H. Patel, R. Y. S. Suda, S. Zhang, P. A. Thistlethwaite, J. X.-J. Yuan, and P. A. Insel Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1 Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L294 - L303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-L. Wong, F. Whelan, P. Deloukas, P. Whittaker, M. Delgado, R. M. Cantor, S. M. McCann, and J. Licinio Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response PNAS, October 10, 2006; 103(41): 15124 - 15129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Gonzalez-Iglesias, Y. Jiang, M. Tomic, K. Kretschmannova, S. A. Andric, H. Zemkova, and S. S. Stojilkovic Dependence of Electrical Activity and Calcium Influx-Controlled Prolactin Release on Adenylyl Cyclase Signaling Pathway in Pituitary Lactotrophs Mol. Endocrinol., September 1, 2006; 20(9): 2231 - 2246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Andric, T. S. Kostic, and S. S. Stojilkovic Contribution of Multidrug Resistance Protein MRP5 in Control of Cyclic Guanosine 5'-Monophosphate Intracellular Signaling in Anterior Pituitary Cells Endocrinology, July 1, 2006; 147(7): 3435 - 3445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Nogueira, R. Ron-El, S. Friedler, M. Schachter, A. Raziel, R. Cortvrindt, and J. Smitz Meiotic Arrest In Vitro by Phosphodiesterase 3-Inhibitor Enhances Maturation Capacity of Human Oocytes and Allows Subsequent Embryonic Development Biol Reprod, January 1, 2006; 74(1): 177 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Hicks, Y.-S. Bahn, and J. Heitman Pde1 Phosphodiesterase Modulates Cyclic AMP Levels through a Protein Kinase A-Mediated Negative Feedback Loop in Cryptococcus neoformans Eukaryot. Cell, December 1, 2005; 4(12): 1971 - 1981. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Seino and T. Shibasaki PKA-Dependent and PKA-Independent Pathways for cAMP-Regulated Exocytosis Physiol Rev, October 1, 2005; 85(4): 1303 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Zhang, Y Tao, B Zhou, H Xie, F Wang, L Lei, L Huo, Q Sun, and G Xia Atrial natriuretic peptide inhibits the actions of FSH and forskolin in meiotic maturation of pig oocytes via different signalling pathways J. Mol. Endocrinol., April 1, 2005; 34(2): 459 - 472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Goraya, N. Masada, A. Ciruela, and D. M. F. Cooper Sustained Entry of Ca2+ Is Required to Activate Ca2+-Calmodulin-dependent Phosphodiesterase 1A J. Biol. Chem., September 24, 2004; 279(39): 40494 - 40504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. TASKEN and E. M. AANDAHL Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A Physiol Rev, January 1, 2004; 84(1): 137 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Nogueira, R. Cortvrindt, D.G. De Matos, L. Vanhoutte, and J. Smitz Effect of Phosphodiesterase Type 3 Inhibitor on Developmental Competence of Immature Mouse Oocytes In Vitro Biol Reprod, December 1, 2003; 69(6): 2045 - 2052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Maurice, D. Palmer, D. G. Tilley, H. A. Dunkerley, S. J. Netherton, D. R. Raymond, H. S. Elbatarny, and S. L. Jimmo Cyclic Nucleotide Phosphodiesterase Activity, Expression, and Targeting in Cells of the Cardiovascular System Mol. Pharmacol., September 1, 2003; 64(3): 533 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Nogueira, C. Albano, T. Adriaenssens, R. Cortvrindt, C. Bourgain, P. Devroey, and J. Smitz Human Oocytes Reversibly Arrested in Prophase I by Phosphodiesterase Type 3 Inhibitor In Vitro Biol Reprod, September 1, 2003; 69(3): 1042 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Park, F. Richard, S.-Y. Chun, J.-H. Park, E. Law, K. Horner, S-L C. Jin, and M. Conti Phosphodiesterase Regulation Is Critical for the Differentiation and Pattern of Gene Expression in Granulosa Cells of the Ovarian Follicle Mol. Endocrinol., June 1, 2003; 17(6): 1117 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Corbin, M. A. Blount, J. L. Weeks II, A. Beasley, K. P. Kuhn, Y. S. J. Ho, L. F. Saidi, J. H. Hurley, J. Kotera, and S. H. Francis [3H]Sildenafil Binding to Phosphodiesterase-5 Is Specific, Kinetically Heterogeneous, and Stimulated by cGMP Mol. Pharmacol., June 1, 2003; 63(6): 1364 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shinozaki, V. Butnev, Y.-X. Tao, K. L. Ang, M. Conti, and D. L. Segaloff Desensitization of Gs-Coupled Receptor Signaling by Constitutively Active Mutants of the Human Lutropin/Choriogonadotropin Receptor J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1194 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Doyle and J. M. Egan Pharmacological Agents That Directly Modulate Insulin Secretion Pharmacol. Rev., March 1, 2003; 55(1): 105 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Conti Specificity of the Cyclic Adenosine 3',5'-Monophosphate Signal in Granulosa Cell Function Biol Reprod, December 1, 2002; 67(6): 1653 - 1661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.T. Jensen, K.M. Schwinof, M.B. Zelinski-Wooten, M. Conti, L.V. DePaolo, and R.L. Stouffer Phosphodiesterase 3 inhibitors selectively block the spontaneous resumption of meiosis by macaque oocytes in vitro Hum. Reprod., August 1, 2002; 17(8): 2079 - 2084. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Huang, Y. Zhang, and J. R. Sportsman A Fluorescence Polarization Assay for Cyclic Nucleotide Phosphodiesterases J Biomol Screen, June 1, 2002; 7(3): 215 - 222. [Abstract] [PDF]
|
|
|
|
|
|
T. S. Kostic, M. Tomic', S. A. Andric, and S. S. Stojilkovic Calcium-independent and cAMP-dependent Modulation of Soluble Guanylyl Cyclase Activity by G Protein-coupled Receptors in Pituitary Cells J. Biol. Chem., May 3, 2002; 277(19): 16412 - 16418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Paglia, H. Mou, and R. H. Cote Regulation of Photoreceptor Phosphodiesterase (PDE6) by Phosphorylation of Its Inhibitory gamma Subunit Re-evaluated J. Biol. Chem., February 8, 2002; 277(7): 5017 - 5023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Moon, R. Lee, R. Near, L. Weintraub, S. Wolda, and A. Lerner Inhibition of PDE3B Augments PDE4 Inhibitor-induced Apoptosis in a Subset of Patients with Chronic Lymphocytic Leukemia Clin. Cancer Res., February 1, 2002; 8(2): 589 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Mayes and M.-A. Sirard Effect of Type 3 and Type 4 Phosphodiesterase Inhibitors on the Maintenance of Bovine Oocytes in Meiotic Arrest Biol Reprod, January 1, 2002; 66(1): 180 - 184. [Abstract] [Full Text]
|
|
|
|
|
|
L. Persani, S. Borgato, A. Lania, M. Filopanti, G. Mantovani, M. Conti, and A. Spada Relevant cAMP-Specific Phosphodiesterase Isoforms in Human Pituitary: Effect of Gs{alpha} Mutations J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3795 - 3800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shitsukawa, C.B. Andersen, F.J. Richard, A.K. Horner, A. Wiersma, M. van Duin, and M. Conti Cloning and Characterization of the Cyclic Guanosine Monophosphate-Inhibited Phosphodiesterase PDE3A Expressed in Mouse Oocyte Biol Reprod, July 1, 2001; 65(1): 188 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Richards New Signaling Pathways for Hormones and Cyclic Adenosine 3',5'-Monophosphate Action in Endocrine Cells Mol. Endocrinol., February 1, 2001; 15(2): 209 - 218. [Abstract] [Full Text]
|
|
|
|
|
|
H. Mou and R. H. Cote The Catalytic and GAF Domains of the Rod cGMP Phosphodiesterase (PDE6) Heterodimer Are Regulated by Distinct Regions of Its Inhibitory gamma Subunit J. Biol. Chem., July 13, 2001; 276(29): 27527 - 27534. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
