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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 9, Number 8, August 2008
Contents
Peripheral Proteins as Drug Targets
Guest Editor: Robert V. Stahelin
Editorial Pp. 601-602
Cellular Membranes and Lipid-Binding Domains as Attractive
Targets for Drug Development Pp. 603-613
C.G. Sudhahar, R.M. Haney, Y. Xue and R.V. Stahelin
[Abstract] [Purchase
Article]
The Life and Death of Protein Kinase C Pp.
614-625
C.M. Gould and A.C. Newton
[Abstract] [Purchase
Article]
Diacylglycerol Kinases as Emerging Potential Drug
Targets for a Variety of Diseases Pp. 626-640
F. Sakane, S.-i. Imai, M. Kai, S. Yasuda and H. Kanoh
[Abstract] [Purchase
Article]
Wealth of Opportunity - The C1 Domain as a Target
for Drug Development Pp. 641-652
P.M. Blumberg, N. Kedei, N.E. Lewin, D. Yang, G. Czifra,
Y. Pu, M.L. Peach and V.E. Marquez
[Abstract] [Purchase
Article]
Molecular Targeting of Acid Ceramidase: Implications
to Cancer Therapy Pp. 653-661
Y.H. Zeidan, R.W. Jenkins, J.B. Korman, X. Liu, L.M. Obeid,
J.S. Norris and Y.A. Hannun
[Abstract] [Purchase
Article]
Targeting SphK1 as a New Strategy against Cancer
Pp. 662-673
D. Shida, K. Takabe, D. Kapitonov, S. Milstien and S.
Spiegel
[Abstract] [Purchase
Article]
Ceramide Kinase and the Ceramide-1-Phosphate/cPLA2α
Interaction as a Therapeutic Target Pp. 674-682
N.F. Lamour and C.E. Chalfant
[Abstract] [Purchase
Article]
Group VI Phospholipases A2:
Homeostatic Phospholipases with Significant Potential as Targets
for Novel Therapeutics Pp. 683-697
W.P. Wilkins III and S.E. Barbour
[Abstract] [Purchase
Article]
Therapeutic Potential of Autotaxin/Lysophospholipase
D Inhibitors Pp. 698-708
L. Federico, Z. Pamuklar, S.S. Smyth and A.J. Morris
[Abstract] [Purchase
Article]
ENaC and Its Regulatory Proteins as Drug Targets for
Blood Pressure Control Pp. 709-716
D. Rotin and L. Schild
[Abstract] [Purchase
Article]
Erratum Pp. 717
Abstracts
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Editorial
More than half of all human proteins are located in (i.e.
receptors and ion channels) or on (i.e. lipid-binding peripheral
proteins) cellular membranes. These proteins function in cell
signaling and membrane trafficking events to maintain cellular
metabolism, growth, differentiation, and homeostasis. Thus,
cellular membranes are a platform for intracellular communication
where different extracellular signals regulate assembly of
lipid-protein and protein-protein complexes. The metabolism
of lipids by lipid phosphatases, kinases, phospholipases and
more enzymes provides cellular membranes with a vast variety
of lipid headgroups and acyl chains for spatial and temporal
recruitment of peripheral proteins to specific membrane sites
in cells. The interactions between lipids and target proteins
are of generally high affinity and specificity and most often
mediated by modular lipid-binding domains [1, 2]. These small
domains (~60-220 amino acids) have unique surface characteristics
such as charge and hydrophobic moieties to dock onto different
lipid membranes. These lipid-binding sites may serve as a
‘hot spot’ for drug development aimed at inhibiting
protein function through abrogation of membrane binding. This
is in contrast to the common target site of most enzyme inhibitors,
the catalytic site, and may provide a more selective means
of inhibiting or activating function of the lipid-dependent
proteins. Recently, this concept was validated with in
silico structure-based virtual ligand screening, which
identified several lipid-binding inhibitors of a C2 domain
[3]. Along with inhibition of lipid binding the different
regions of cellular membranes (i.e. polar and nonpolar) represent
target sites of potential therapeutic agents that could specifically
disrupt or accentuate lipid-protein interactions within the
bilayer [4]. The rapidly expanding field of interdisciplinary
research surrounding biomembranes warrants a timely overview
of lipid-dependent drug targets as well as strategies of targeting
their inhibition and/or activation. Thus, this edition of
Current Drug Targets is intended to bring together recent
findings and novel concepts about peripheral proteins and
their potential as drug targets.
In the introductory article, the Stahelin lab provides an
overview of the structure and function of lipid-protein interactions
highlighting important peripheral protein drug targets and
strategies of targeting both the peripheral proteins and membranes.
The introductory article is followed by three reviews centering
on the lipid second messenger diacylglycerol (DAG). DAG signals
act as modulators of cell growth and apoptosis through interactions
with a zinc finger DAG recognition motif known as the C1 domain.
This is first addressed by Christine Gould and Alexandra Newton
as they provide a wonderful overview of the DAG binding protein
kinase C (PKC) family of proteins and their regulation by
lipids, phosphorylation, scaffolding proteins and ubiquitin.
They also describe current and future strategies of targeting
PKCs and their regulatory proteins. Next, Fumio Sakane and
colleagues highlight the mechanisms of diacylglycerol kinase
(DGKs) regulation and their metabolism of DAG to phosphatidic
acid. The authors discuss with keen insight the basis for
DGKs as drug targets in diseases such as cancer, epilepsy,
and autoimmune diseases. In the final installment of DAG signaling
Peter Blumberg and colleagues present a seminal article on
targeting the DAG binding C1 domain in drug development. Here
the authors present the potential of the C1 domain as a drug
target and draw attention to current therapeutics in clinical
trials aimed at C1 domain targeting.
Sphingolipids are a class of bioactive lipids that have received
much attention in the last two decades as important regulators
of cancer. In fact, enzymes associated with sphingolipid synthesis
such as sphingosine kinase 1 (SK) [5] and ceramide kinase
(CerK) [6] have been classified as peripheral proteins due
to their ability to bind cellular membranes. Thus, three articles
are included here to highlight the dynamic field of sphingolipids
and some of the important drug targets involved in sphingolipid
synthesis and/or degradation. In the first article, Yusuf
Hannun, Youssef Zeidan and colleagues discuss the molecular
targeting of acid ceramidase in cancer therapy. Acid ceramidase
is a lipid hydrolase that is able to regulate ceramide and
sphingosine-1-phosphate levels, traditionally two bioactive
lipids in cancer among other diseases. Hannun, Zeidan and
colleagues outline this enzyme from the gene to the protein
in an astute and timely fashion. Next, Sarah Spiegel, Dai
Shida and colleagues summarize SK and its role in cancer.
The authors carefully and creatively address the properties
of SK, its role in different types of cancers, and current
inhibitor and clinical trial compounds of SK activity. Finally,
Charles Chalfant and Nadia Lamour review CerK synthesis of
ceramide-1-phosphate (C1P) and the subsequent activation of
cytosolic phospholipase A2α
(cPLA2α).
Chalfant and Lamour keenly describe the regulatory mechanisms
of CerK and its mode of synthesizing C1P. The authors then
go on to describe the biological role of C1P and the potential
of CerK, C1P and cPLA2α
as therapeutic targets.
New avenues in bioactive lipids research are constantly being
explored unveiling new signaling cascades harboring peripheral
protein drug targets. Thus, we have included some topics where
the role of lipid-protein interactions is less well understood
but certainly a viable target in drug development. In the
first hot topic, Suzanne Barbour and W. P. Wilkins discuss
group VI phospholipases A2
and their potential as drug targets. These enzymes are acyl
hydrolases that can target the sn-2 fatty acid backbone
of glycerophospholipids in a Ca2+ -independent
manner. The authors discuss this class of enzymes’ structure,
function, and targeting potential in muscular dystrophy, cancer,
allergy, and bacterial and fungal infections among others
diseases. Next, Andrew Morris and colleagues provide a timely
update to lysophosphatidic acid (LPA) signaling. The authors
superbly outline LPA signaling in health and disease and draw
attention to autotaxin, a secreted enzyme in the extracellular
LPA synthesis pathway. Pharmacological inhibition of autotaxin
is thought to be a potentially effective way of interfering
with LPA signaling in the cardiovascular system as well as
in tumor metastasis. Lastly, Daniela Rotin and Laurent Schild
describe a mechanism of targeting hypertension through the
Epithelial Na+ Channel (ENaC).
ENaC is regulated by the ubiquitin ligase Nedd4-2, which ubiquitylates
the channel and targets it for endocytosis. When the interaction
between Nedd4-2 and ENaC is impaired, Liddle syndrome results,
which is characterized by hypertension. Interestingly, Nedd4-2
is a lipid-binding protein but the role of lipids in the recycling
of the ENaC is only beginning to be explored. This review
should serve as a stepping-stone to explore and understand
the role of plasma membrane lipids in Nedd4-2 recruitment
and ENaC activity.
I would like to thank all the contributors for their efforts
in providing their outstanding reviews, which I anticipate
will shed some light on drug targets regulated by interactions
with cellular membranes. This edition by no means encompasses
all peripheral proteins that are drug targets but it is hoped
that these articles will bring together current biochemical,
biophysical and biological data on dynamic intracellular communication
and interactions on cellular membranes. This should help readers
gain a better understanding of how peripheral proteins are
regulated as well as future novel strategies of targeting
these lipid-binding proteins. The rapidly expanding field
of interdisciplinary research at the membrane interface including
lipidomics, bioinformatics, rapid cell and small molecule
screening as well as single molecule studies will lead to
identification of new bioactive lipids, receptors and peripheral
proteins that are drug targets. In turn, this will lead to
a deeper understanding of lipid signaling and regulation of
peripheral proteins hopefully bringing more drugs to market
in a timely fashion.
References
[1] Cho, W. and Stahelin, R.V. (2005) Annu. Rev. Biophys.
Biomol. Struct., 34, 119-151.
[2] Lemmon, M.A. (2008) Nat. Rev. Mol. Cell. Biol.,
9(2), 99-111.
[3] Segers, K.; Sperandio, O.; Sack, M.; Fischer, R.; Miteva,
M.A.; Rosing, J.; Nicolaes, G.A. and Villoutreix, B.O. (2007)
Proc. Natl. Acad. Sci. USA, 104(31),
12697-12702.
[4] Hanshaw, R.G.; Stahelin, R.V. and Smith, B.D. (2008) Chemistry,
14(6), 1690-1697.
[5] Stahelin, R.V.; Hwang, J.H.; Kim, J.H.; Park, Z.Y.; Johnson,
K.R.; Obeid, L.M. and Cho, W. (2005) J. Biol. Chem.,
280(52), 43030-43038.
[6] Lamour, N.; Stahelin, R.V.; Wijesinghe, D.S.; Maceyka,
M.; Wang, E.; Allegood, J.C.; Merrill, A.H., Jr.; Cho, W.
and Chalfant, C.E. (2007) J. Lipid Res., 48(6),
1293-1304.
Robert V. Stahelin
Department of Biochemistry and Molecular Biology
Indiana University School of Medicine-South Bend
South Bend, IN, 46617
and
Department of Chemistry and Biochemistry and
the Walther Center for Cancer Research
Notre Dame, IN 46656
USA
Tel: 1-574-631-5054
Fax: 1-574-631-7821
E-mail: rstaheli@iupui.edu
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Article]
Cellular Membranes and Lipid-Binding Domains as Attractive
Targets for Drug Development
C.G. Sudhahar, R.M. Haney, Y. Xue and R.V. Stahelin
Interdisciplinary research focused on biological membranes
has revealed them as signaling and trafficking platforms for
processes fundamental to life. Biomembranes harbor receptors,
ion channels, lipid domains, lipid signals, and scaffolding
complexes, which function to maintain cellular growth, metabolism,
and homeostasis. Moreover, abnormalities in lipid metabolism
attributed to genetic changes among other causes are often
associated with diseases such as cancer, arthritis and diabetes.
Thus, there is a need to comprehensively understand molecular
events occurring within and on membranes as a means of grasping
disease etiology and identifying viable targets for drug development.
A rapidly expanding field in the last decade has centered
on understanding membrane recruitment of peripheral proteins.
This class of proteins reversibly interacts with specific
lipids in a spatial and temporal fashion in crucial biological
processes. Typically, recruitment of peripheral proteins to
the different cellular sites is mediated by one or more modular
lipid-binding domains through specific lipid recognition.
Structural, computational, and experimental studies of these
lipid-binding domains have demonstrated how they specifically
recognize their cognate lipids and achieve subcellular localization.
However, the mechanisms by which these modular domains and
their host proteins are recruited to and interact with various
cell membranes often vary drastically due to differences in
lipid affinity, specificity, penetration as well as protein-protein
and intramolecular interactions. As there is still a paucity
of predictive data for peripheral protein function, these
enzymes are often rigorously studied to characterize their
lipid-dependent properties. This review summarizes recent
progress in our understanding of how peripheral proteins are
recruited to biomembranes and highlights avenues to exploit
in drug development targeted at cellular membranes and/or
lipid-binding proteins.
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The Life and Death of Protein Kinase C
C.M. Gould and A.C. Newton
Protein kinase C (PKC) is a family of kinases that plays
diverse roles in many cellular functions, notably proliferation,
differentiation, and cell survival. PKC is processed by phosphorylation
and regulated by cofactor binding and subcellular localization.
Extensive detail is available on the molecular mechanisms
that regulate the maturation, activation, and signaling of
PKC. However, less information is available on how signaling
is terminated both from a global perspective and isozyme-specific
differences. To target PKC therapeutically, various ATP-competitive
inhibitors have been developed, but this method has problems
with specificity. One possible new approach to developing
novel, specific therapeutics for PKC would be to target the
signaling termination pathways of the enzyme. This review
focuses on the new developments in understanding how PKC signaling
is terminated and how current drug therapies as well as information
obtained from the recent elucidation of various PKC structures
and down-regulation pathways could be used to develop novel
and specific therapeutics for PKC.
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Diacylglycerol Kinases as Emerging Potential Drug Targets
for a Variety of Diseases
F. Sakane, S.-i. Imai, M. Kai, S. Yasuda and H. Kanoh
Diacylglycerol (DAG) kinase (DGK) modulates the balance
between the two signaling lipids, DAG and phosphatidic acid
(PA), by phosphorylating (consuming) DAG to yield PA. Ten
mammalian DGK isozymes have been identified to date. In addition
to two or three cysteine-rich C1 domains (protein kinase C-like
zinc finger structures) commonly conserved in all DGKs, these
isoforms possess a variety of regulatory domains of known
and/or predicted functions, such as a pair of EF-hand motifs,
a pleckstrin homology domain, a sterile α
motif domain, a MARCKS (myristoylated alanine-rich C kinase
substrate) phosphorylation site domain and ankyrin repeats.
Recent studies have revealed that DGK isozymes play pivotal
roles in a wide variety of mammalian signal transduction pathways
conducting growth factor/cytokine-dependent cell proliferation
and motility, seizure activity, immune responses, cardiovascular
responses and insulin receptor-mediated glucose metabolism.
It is suggested that several DGK isozymes can serve as potential
drug targets for cancer, epilepsy, autoimmunity, cardiac hypertrophy,
hypertension and type II diabetes. Unfortunately, there are
no DGK isozyme-specific inhibitors/activators at present.
Development of these compounds is eagerly awaited for the
development of novel drugs targeting DGKs.
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Wealth of Opportunity - The C1 Domain as a Target for Drug
Development
P.M. Blumberg, N. Kedei, N.E. Lewin, D. Yang, G. Czifra,
Y. Pu, M.L. Peach and V.E. Marquez
The diacylglycerol-responsive C1 domains of protein kinase
C and of the related classes of signaling proteins represent
highly attractive targets for drug development. The signaling
functions that are regulated by C1 domains are central to
cellular control, thereby impacting many pathological conditions.
Our understanding of the diacylglycerol signaling pathways
provides great confidence in the utility of intervention in
these pathways for treatment of cancer and other conditions.
Multiple compounds directed at these signaling proteins, including
compounds directed at the C1 domains, are currently in clinical
trials, providing strong validation for these targets. Extensive
understanding of the structure and function of C1 domains,
coupled with detailed insights into the molecular details
of ligand – C1 domain interactions, provides a solid
basis for rational and semi-rational drug design. Finally,
the complexity of the factors contributing to ligand –
C1 domain interactions affords abundant opportunities for
manipulation of selectivity; indeed, substantially selective
compounds have already been identified.
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Molecular Targeting of Acid Ceramidase: Implications to Cancer
Therapy
Y.H. Zeidan, R.W. Jenkins, J.B. Korman, X. Liu, L.M. Obeid,
J.S. Norris and Y.A. Hannun
Increasingly recognized as bioactive molecules, sphingolipids
have been studied in a variety of disease models. The impact
of sphingolipids on cancer research facilitated the entry
of sphingolipid analogues and enzyme modulators into clinical
trials. Owing to its ability to regulate two bioactive sphingolipids,
ceramide and sphingosine-1-phosphate, acid ceramidase (AC)
emerges as an attractive target for drug development within
the sphingolipid metabolic pathway. Indeed, there is extensive
evidence supporting a pivotal role for AC in lipid metabolism
and cancer biology. In this article, we review the current
knowledge of the biochemical properties of AC, its relevance
to tumor promotion, and its molecular targeting approaches.
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Targeting SphK1 as a New Strategy against Cancer
D. Shida, K. Takabe, D. Kapitonov, S. Milstien and S.
Spiegel
Sphingolipid metabolites have emerged as critical players
in a number of fundamental biological processes. Among them,
sphingosine-1-phosphate (S1P) promotes cell survival and proliferation,
in contrast to ceramide and sphingosine, which induce cell
growth arrest and apoptosis. These sphingolipids with opposing
functions are interconvertible inside cells, suggesting that
a finely tuned balance between them can determine cell fate.
Sphingosine kinases (SphKs), which catalyze the phosphorylation
of sphingosine to S1P, are critical regulators of this balance.
Of the two identified SphKs, sphingosine kinase type 1 (SphK1)
has been shown to regulate various processes important for
cancer progression and will be the focus of this review, since
much less is known of biological functions of SphK2, especially
in cancer. SphK1 is overexpressed in various types of cancers
and upregulation of SphK1 has been associated with tumor angiogenesis
and resistance to radiation and chemotherapy. Many growth
factors, through their tyrosine kinase receptors (RTKs), stimulate
SphK1 leading to a rapid increase in S1P. This S1P in turn
can activate S1P receptors and their downstream signaling.
Conversely, activation of S1P receptors can induce transactivation
of various RTKs. Thus, SphK1 may play important roles in S1P
receptor RTK amplification loops. Here we review the role
of SphK1 in tumorigenesis, hormonal therapy, chemotherapy
resistance, and as a prognostic marker. We will also review
studies on the effects of SphK inhibitors in cells in
vitro and in animals in vivo and in some clinical
trials and highlight the potential of SphK1 as a new target
for cancer therapeutics.
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Ceramide Kinase and the Ceramide-1-Phosphate/cPLA2α
Interaction as a Therapeutic Target
N.F. Lamour and C.E. Chalfant
Ceramide kinase (CERK) was discovered more than a decade
ago. Since then, numerous reports have been published demonstrating
a role for CERK in various signal transduction pathways involved
in inflammation, immunity or cancer. In this review, the biosynthesis
of ceramide-1-phosphate (C1P) and the various roles of CERK
and C1P in biological mechanisms will be overviewed. We will
focus on the role of C1P in eicosanoid synthesis, more specifically,
in the activation and translocation of cPLA2α.
Furthermore, the possible therapeutic relevance of inhibitors
of these mechanisms is discussed.
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Group VI Phospholipases A2:
Homeostatic Phospholipases with Significant Potential as Targets
for Novel Therapeutics
W.P. Wilkins III and S.E. Barbour
Group VI phospholipase A2
(PLA2) is a family of acyl
hydrolases that targets the sn-2 fatty acid on the
glyc-erophospholipid (GPL) backbone. These enzymes are grouped
together based on structural homologies and catalytic ac-tivities
that are independent of calcium and hence are also called
the iPLA2s. Although the
best characterized of these enzymes, iPLA2β
and iPLA2γ,
have long been proposed as homeostatic enzymes involved in
basal GPL metabolism, recent studies indicate roles for these
enzymes in biomedically relevant processes as well. For example,
iPLA2 modulates calcium homeostasis
by promoting replenishment of intracellular calcium stores.
This function is likely of importance in the pathogenesis
of Duchenne muscular dystrophy and potentially allergy as
well. iPLA2 has a variety
of roles in bacterial pathogenesis and the host response against
bacterial and fungal infections. These characteristics suggest
that the enzyme as a potential target to control infectious
diseases. iPLA2 is linked
to both proliferation and chemotherapy-induced apoptosis of
tumor cells. As such, the enzyme is a potential target for
cancer chemotherapy. Recent studies indicate essential roles
for iPLA2 in glucose homeostasis,
maintenance of energy balance, adipocyte development, and
hepatic lipogenesis. Thus, the enzyme is an attractive target
for drugs to control type II diabetes, fatty liver disease,
and other manifestations of the metabolic syndrome. Several
recent studies have associated iPLA2
inactivation with neurodegenerative diseases, suggesting the
possibility that products of the iPLA2
reaction as potential treatments for these disorders. Together,
these observations suggest iPLA2
as a novel and important target for drug development. However
given the ubiquitous expression of the enzyme and its roles
in basal GPL metabolism, drug strategies targeting iPLA2must
exhibit exquisite selectivity to avoid undesired side effects.
Furthermore, the cell-specific nature of many iPLA2
functions may present another challenge in the design and
implementation of drugs targeted to the enzyme.
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Therapeutic Potential of Autotaxin/Lysophospholipase D Inhibitors
L. Federico, Z. Pamuklar, S.S. Smyth and A.J. Morris
Lysophosphatidic acids (LPAs) are structurally simple
lipid phosphate esters with a widely appreciated role as extracellular
signaling molecules. LPA binds to selective cell surface receptors
to promote cell growth, survival, motility and differentiation.
Studies using LPA receptor knockout mice and experimental
therapeutics targeting these receptors identify roles for
LPA signaling in processes that include cardiovascular disease
and function, angiogenesis, reproduction, cancer progression
and neuropathic pain. These studies identify considerable
functional redundancy between these receptors and raise the
possibility that additional lysophosphatidic acid receptors
remain to be identified. LPA is present in the blood and other
biological fluids at physiologically relevant concentrations
and can likely be rapidly generated and degraded in different
locations, for example at sites of inflammation, vascular
injury and thrombosis or in the tumor micro environment. Recent
work identifies a secreted enzyme, autotaxin (ATX), as the
key component of an extracellular pathway for generation of
lysophosphatidic acid by lysophospholipase D catalyzed hydrolysis
of lysophospholipid substrates. In contrast to the apparently
redundant functions of LPA receptors, studies using ATX knock
out and transgenic mice indicate that this enzyme is uniquely
required for LPA signaling during early development and serves
as the primary determinant of circulating LPA levels in adult
animals. Accordingly, pharmacological inhibition of ATX may
be a viable and potentially effective way to interfere with
LPA signaling in the cardiovascular system and possibly other
settings such as tumor metastasis for therapeutic benefit.
In this review we provide an update on recent advances in
defining roles for LPA signaling in major disease processes
and discuss recent progress in understanding the regulation
and function of autotaxin focusing on strategies for the identification
and initial evaluation of small molecule autotaxin inhibitors.
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ENaC and Its Regulatory Proteins as Drug Targets for Blood
Pressure Control
D. Rotin and L. Schild
Hypertension is a serious medical problem affecting millions
of people worldwide. A key protein regulating blood pressure
is the Epithelial Na+ Channel
(ENaC). In accord, loss of function mutations in ENaC (PHA1)
cause hypotension, whereas gain of function mutations (Liddle
syndrome) result in hypertension. The region mutated in Liddle
syndrome, called the PY motif (L/PPxY), serves as a binding
site for the ubiquitin ligase Nedd4-2, a C2-WW-Hect E3 ubiquitin
ligase. Nedd4-2 binds the ENaC-PY motif via it WW
domains, ubiquitylates the channel and targets it for endocytosis,
a process impaired in Liddle syndrome due to poor binding
of the channel to Nedd4-2. This leads to accumulation of active
channels at the cell surface and increased Na+
(and fluid) absorption in the distal nephron, resulting in
elevated blood volume and blood pressure. Compounds that destabilize
cell surface ENaC, or enhance Nedd4-2 activity in the kidney,
could potentially serve as drug targets for hypertension.
In addition, recent discoveries of regulation of activation
of ENaC by proteases such as furin, prostasin and elastase,
which cleave the extracellular domain of this channel leading
to it activation, as well as the identification of inhibitors
that block the activity of these proteases, provide further
avenues for drug targeting of ENaC and the control of blood
pressure.
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