Department of Physiology, University of California at San Francisco School of Medicine, 513 Parnassus Avenue, San Francisco, CA 94143-0444, USA
(e-mail: bredt{at}phy.ucsf.edu)
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Summary |
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Key words: Nitric oxide, Heart, Protein targeting, PDZ domain
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Introduction |
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The primary mechanism controlling the neuronal NOS (nNOS) and the
endothelial NOS (eNOS) enzymes is increased levels of intracellular calcium
(Knowles et al., 1989;
Palmer and Moncada, 1989
),
which activates these NOS isoforms by binding to calmodulin
(Bredt and Snyder, 1990
;
Pollock et al., 1991
), which
in turn interacts with NOS. To enhance specificity for responses to calcium,
NOS enzymes concentrate in specific subcellular domains. This allows NOS
activity to respond selectively to calcium mobilization from localized calcium
pools. Furthermore, diverse protein interactions and post-translational
modifications, including protein phosphorylation and lipid modification of the
enzyme, modify NOS isoforms to control their activation by upstream signal
transduction events. The reactive and diffusive nature of the NO signal also
requires that the synthase be localized in proximity to its downstream
targets. This enhances signaling specificity for the reactive NO mediator and
minimizes toxicity that arises from the free radical nature of NO.
Here, we highlight recent studies showing the importance of subcellular targeting and protein interactions of NOS in controlling both upstream and downstream signaling by the unique mediator NO.
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nNOS association with dystrophin skeletal muscle |
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NO derived from nNOSµ in skeletal muscle fibers plays a major role in
dilating blood vessels adjacent to contracting skeletal muscle
(Thomas and Victor, 1998).
This physiological response, functional hyperemia, plays an important role in
increasing blood flow to contracting skeletal muscles to support their
enhanced metabolic needs. Targeting nNOSµ to the sarcolemmal dystrophin
complex specifies both upstream and downstream signaling by NO in this pathway
(Fig. 1) that is,
localization of NO at the sarcolemma is critical for coupling calcium influx
associated with muscle contraction to NO synthesis. Formation of NO at the
muscle membrane facilitates its diffusion to the adjacent vascular smooth
muscle (Thomas et al., 1998
).
The target for NO in smooth muscle is the soluble isoform of guanylyl cyclase,
whose activity is increased 100-fold by its binding to NO; the elevated cGMP
levels then mediate blood vessel dilation
(Hobbs and Ignarro, 1996
;
McDonald and Murad, 1995
).
|
The molecular mechanism for association of nNOS with the sarcolemmal
dystrophin complex involves an N-terminal PDZ domain of nNOS
(Brenman et al., 1996). PDZ
domains are small modular proteinprotein interaction interfaces that
mediate assembly of protein complexes at cell junctions. These domains are
ubiquitous and occur in a variety of dissimilar enzymes and cytoskeletal
adaptor proteins. In fact the recently sequenced human genome boasts over 150
PDZ containing proteins (Schultz et al.,
2000
). Amongst the NOS isoforms, nNOS is unique in containing a
PDZ domain, and this domain plays a major role in targeting the nNOS to
specific cellular membranes (Brenman and
Bredt, 1997
).
Structurally, PDZ domains are compact globular modules that contain a
single binding pocket that typically interacts with protein ligands that end
with a specific PDZ-binding C-terminal consensus sequence
(Craven and Bredt, 1998;
Doyle et al., 1996
;
Garner et al., 2000
;
Harris et al., 2002
;
Kornau et al., 1997
;
Sheng, 2001
). However,
biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a
similar PDZ domain of syntrophin (Fig.
1), a dystrophin-associated protein
(Brenman et al., 1996
). This
association of nNOS with syntrophin differs from canonical C-terminal PDZ
interactions in that it involves two PDZ domains that form a heterodimer.
X-ray crystallographic studies of the nNOSsyntrophin complex showed
that a ß-finger projection from the nNOS PDZ domain fits into the
syntrophin PDZ binding pocket and makes contacts that resemble those formed by
a typical C-terminal peptide ligand
(Hillier et al., 1999
). This
prototypical PDZ heterodimer structure of nNOSsyntrophin helps to
explain numerous examples of PDZ domains binding to internal protein binding
sites (Hillier et al.,
1999
).
This nNOSsyntrophin PDZPDZ complex is essential for
sarcolemmal association of nNOS, since mutant mice lacking syntrophin show a
selective loss of nNOS from the skeletal muscle plasma membrane
(Adams et al., 2001;
Kameya et al., 1999
).
Sarcolemmal localization of nNOS is also lost in patients with Duchenne
muscular dystrophy, which is due to genetic disruption of dystrophin
(Brenman et al., 1995
). The
loss of dystrophin in muscular dystrophy prevents assembly of the dystrophin
glycoprotein complex. As a result, NO signaling in response to muscle
contraction is disrupted (Brenman et al.,
1995
), and, the blood vessel dilation of contracting skeletal
muscle that is normally mediated by NO is abolished
(Thomas et al., 1998
).
Recent studies show that disruption of NO signaling plays a major role in
muscular dystrophy pathophysiology. Transgenic overexpression of nNOS in
skeletal muscle of mdx mice, which lack dystrophin, rescues much of
the muscle pathology and enhances muscle function
(Wehling et al., 2001).
Furthermore, certain mutations of the dystrophin complex that cause a mild
muscular dystrophy uniquely disrupt sarcolemmal nNOS
(Bredt, 1999
). In patients with
Beckers muscular dystrophy due to mutations in the spectrin-like domains of
dystrophin, and in mutant mice lacking the dystrophin-associated dystrobrevin,
nNOS but not other components of the dystrophin complex are lost from the
sarcolemma (Chao et al., 1996
;
Grady et al., 1999
). Curiously
however, mutant mice lacking nNOS do not show muscular dystrophy
(Chao et al., 1998
;
Crosbie et al., 1998
). Taken
together, these studies suggest that whereas loss of skeletal muscle NO does
not itself cause dystrophy, the lack of nNOS in Duchenne muscular dystrophy
augments the damage caused by absence of the structural dystrophin
glycoprotein complex. Because restoring nNOS ameliorates muscle injury in
muscular dystrophy (Wehling et al.,
2001
), NO donors may offer a potential avenue for therapy.
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nNOS association with NMDA receptors |
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The nNOS PDZ domain binds PSD-95 through the same ß-finger region that
mediates binding to syntrophin in skeletal muscle
(Tochio et al., 2000). In
addition, the nNOS PDZ domain but has its own binding groove that can
associate with specific C-terminal protein ligands to assemble more elaborate
protein complexes (Stricker et al.,
1997
). One prominent binding partner for the nNOS PDZ domain is
CAPON (Jaffrey et al., 1998
),
an adaptor protein that contains both a C-terminal region that binds to the
PDZ domain nNOS and an N-terminal phosphotyrosine binding (PTD) domain. This
PTD domain binds to the small monomeric G protein Dexras1
(Wehling et al., 2001
).
Importantly, NO can activate Dexras1 via S-nitrosylation, and this pathway
(Fig. 2) for downstream
signaling requires the adaptor protein CAPON
(Fang et al., 2000
).
Some nNOS is also present at the presynaptic nerve terminal, where NO may
regulate neurotransmitter release (Meffert
et al., 1996). In nerve terminals of parallel fibers from
cerebellar granule cells, nNOS is apparently regulated by presynaptic NMDA
receptors to regulate Purkinje cell long-term depression, a cellular model for
motor learning (Casado et al.,
2002
; Daniel et al.,
1998
; Lev-Ram et al.,
1997
). Protein interactions with CAPON have also been shown to
target the enzyme to the nerve terminal, where CAPON interacts with synapsins
I, II and III (Jaffrey et al.,
2002
).
Whereas small amounts of NO formed in association with synaptic activity
mediate physiological functions, the overproduction of NO that occurs in
association with specific toxic processes, such as cerebral ischemia, cause
brain injury (Dawson et al.,
1991). Again, the stimulus for NO production in these conditions
is activation of the NMDA receptor, which occurs to excess in such
`excitotoxic' conditions (Coyle and
Puttfarcken, 1993
). The NMDA receptornNOS pathway is a
major pharmaceutical target, and a plethora of NMDA receptor and nNOS
antagonists have been characterized and evaluated as possible therapies for
excitotoxicity (Lipton and Rosenberg,
1994
). However, NMDA receptors and NOS mediate diverse effects; so
simple receptor or enzyme antagonists show severe side effects
(Olney et al., 1989
). The
functional nNOSPSD-95NMDA complex described above provides a new
target for preventing neurotoxicity. Drugs that target this complex could
provide neuroprotection from strokes and other neurodegenerative diseases
while minimizing peripheral side effects. Indeed, downregulation of PSD-95
with antisense oligonucleotides protects cultured neurons from NMDA-mediated
damage (Sattler et al., 1999
).
It will now be important to test whether compounds that block assembly of the
PSD-95nNOSNMDA complex can provide neuroprotection in vivo.
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Subcellular targeting and regulation of eNOS |
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Rather than being homogeneously distributed at the plasma membrane, eNOS is
specifically targeted to the Golgi complex and to plasma membrane caveolae
(Garcia-Cardena et al., 1996b;
Shaul et al., 1996
),
flask-shaped invaginations of the plasma membrane. Caveolae are specifically
enriched with signaling molecules, including G-protein-coupled receptors as
well as ion channels and pumps specifically involved in regulating
intracellular calcium (Anderson,
1998
; Lisanti et al.,
1995
). Dual lipidation of eNOS by the long chain palmitate fatty
acids mediates targeting to caveolae
(Garcia-Cardena et al., 1996b
;
Shaul et al., 1996
), which
have a specialized lipid composition rich in cholesterol and sphingomyelin
that is favorable for incorporation of dually acylated proteins.
Multiple protein interactions in caveolae regulate eNOS activity and its
coupling to extracellular stimuli (Fig.
3). eNOS interacts with the major protein of caveolae, caveolin,
which inhibits eNOS (Feron et al.,
1996; Garcia-Cardena et al.,
1996a
; Ju et al.,
1997
). Mutant mice lacking caveolin-1 have an absence of
plasmalemmal caveolae and show enhanced eNOS activity, which fits with
inhibition of eNOS by caveolin (Drab et
al., 2001
). Caveolin inhibition of eNOS is relieved by calmodulin,
which causes dissociation of eNOS from caveolin. This regulatory mechanism is
further modified by heat shock protein 90 (Hsp90), which binds to eNOS and
facilitates displacement of caveolin by calmodulin
(Gratton et al., 2000
). Hsp90
associates with eNOS at rest, and stimulation with vascular endothelial growth
factor (VEGF), histamine or shear stress increases the hsp90eNOS
interaction (Brouet et al.,
2001
; Garcia-Cardena et al.,
1998
), which further promotes its dissociation from caveolin and
enhances its calmodulin-dependent activity.
|
In addition to these protein interactions that modulate calmodulin binding,
other cellular signaling cascades also regulate eNOS activity. Shear stress,
isometric vessel contraction, insulin and VEGF activate eNOS without
increasing intracellular calcium (Ayajiki
et al., 1996; Fleming et al.,
1999
). A role for phosphorylation in these pathways was first
suggested by pharmacological studies showing that inhibitors of
phosphoinositide 3-kinase (PI-3K) block insulin and VEGF stimulation of eNOS
(Papapetropoulos et al., 1997
;
Zeng and Quon, 1996
). These
effects are explained by activation of the protein kinase Akt by the
3-phosphorylated inositol lipids generated by PI-3K. Akt directly
phosphorylates eNOS at Ser1177 and activates the enzyme 15-20-fold
(Dimmeler et al., 1999
;
Fulton et al., 1999
). Mutation
of Ser1177 to aspartate to mimic the negative charge of phosphorylation yields
an eNOS that is constitutively active
(Dimmeler et al., 1999
) at low
levels of calcium (10 nM), whereas mutation of Ser1177 to alanine prevents
Akt-dependent regulation of eNOS (Fulton
et al., 1999
).
![]() |
Cellular mechanisms controlling NO signaling in heart |
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Targeting of nNOSµ to the sarcoplasmic reticulum versus caveolar
targeting of eNOS can therefore explain the opposing influences of these NOS
isoforms on the heart (Fig. 4).
As shown in the recent study by Hare and collaborators, mutant mice lacking
specific NOS isoforms have opposite changes in cardiac function
(Barouch et al., 2002). At
baseline, nNOS-knockout mice (which also lack nNOSµ) have relatively normal
cardiovascular function whereas eNOS-knockout mice have high blood pressure,
an elevated heart rate and enlarged left ventricular chambers. Importantly,
nNOS-knockout mice exhibit a suppressed ionotropic response to
ß-adrenergic stimulation, whereas eNOS mice show an enhanced response to
isoproterenol. These effects on cardiac function reflect changes in myocyte
calcium cycling such that myocytes from nNOS knockout mice show attenuated
responses to isoproterenol whereas cells from eNOS mutants show enhanced
responses. Interestingly, mice lacking both nNOS and eNOS show defects in
calcium cycling that resembles that of nNOS, which suggests the nNOS effects
in heart predominate.
|
Abnormalities in sarcoplasmic reticulum calcium cycling often cause cardiac
hypertrophy. Indeed nNOS knockout mice show age-related left ventricular
hypertrophy. eNOS knockouts also show left ventricular hypertrophy though it
is associated with hypertension. Mutant mice lacking both nNOS and eNOS show
greater cardiac hypertrophy than either single mutant
(Barouch et al., 2002). This
additivity in the cardiac phenotype emphasizes the independent roles of nNOS
and eNOS in cardiac function and suggests a lack of cross-talk in the
signaling in cardiomyocytes. Since cardiac hypertrophy is often associated
with heart failure and myocardial infarction, modulation of NO level in heart
seems a valuable therapeutic target.
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Perspectives |
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Acknowledgments |
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References |
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