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Department of Physiology, University of California at San Francisco School of Medicine, San Francisco, California
Received March 11, 2003; accepted March 17, 2003
The remarkable discovery of endothelial derived relaxing factor by
Furchgott and Zawadzki (1980
)
initiated research that ultimately led to the discovery of nitric oxide (NO)
as an endogenous mediator (Ignarro,
1993; Moncada and Higgs,
1993; McDonald and Murad,
1995). In the vascular system, NO diffuses from its site of
synthesis in endothelial cells and enters the surrounding smooth muscle, where
it binds to the soluble isoform of guanylyl cyclase (sGC). NO binding
dramatically increases sGC activity to produce cGMP, and this leads to smooth
muscle relaxation.
Although first discovered as a signaling molecule in the vasculature, the
highest levels of NO occur in neurons, where NO functions as a unique
neurotransmitter (Garthwaite,
1991; Snyder and Bredt,
1991). The high levels of NOS in neurons facilitated the initial
identification of a nitric-oxide synthase from neurons
(Bredt et al., 1991).
Neuron-derived NO serves as a major neurotransmitter whose functions are best
characterized in the peripheral nervous system. Release of NO from enteric
neurons dilates gastric and intestinal smooth muscle
(Desai et al., 1991), and
release of NO from neurons in the corpora cavernosa dilates vessels that
mediate penile erection (Burnett et al.,
1992; Rajfer et al.,
1992). In fact, sildenafil (Viagra) treats erectile dysfunction by
functioning as a cGMP phosphodiesterase inhibitor that prolongs the actions of
NO to increase penile blood flow.
Whereas actions of neuron-derived NO outside the brain are well
established, the roles for NO in the central nervous system have been more
difficult to determine. As a free radical gas, NO is a unique messenger
molecule that can readily penetrate cells and tissues. This property of NO
suggested that it would be ideally suited to mediate actions at brain
synapses, the sites at which neurons communicate with each other. Indeed, a
number of studies showed that NO is critically involved in long-term
potentiation (LTP), a form of synaptic plasticity in the hippocampus
(Bohme et al., 1991;
Schuman and Madison, 1991), a
brain region essential for memory formation. LTP can be elicited by providing
a strong stimulus (or tetanus) to Schaffer collateral fibers that innervate
pyramidal cells in the CA1 region of hippocampus. After this tetanus, the
synapses that were stimulated in the CA1 region are specifically strengthened,
and this plasticity may participate in learning and memory functions by the
hippocampus. A role for NO in LTP was first suggested by pharmacological
experiments showing that NOS inhibitors do not alter baseline synaptic
transmission but can completely prevent the LTP
(Bohme et al., 1991;
Schuman and Madison,
1991).
However, the role of NO in LTP has been mired in controversy; numerous labs
have found that LTP can occur in the absence of NO signaling
(Selig et al., 1996).
Furthermore, mutant mice that lack NOS in brain show largely intact LTP in
hippocampus (Son et al.,
1996). In a report of a new study beginning on page 1322 of this
issue of Molecular Pharmacology, Chien et al.
(2003) provide the latest
argument to this controversy. The authors show that a recently discovered
drug, YC-1, which sensitizes the sGC toward activation by NO, dramatically
augments induction of hippocampal LTP. In addition to suggesting that NO may
participate in LTP, this study demonstrates a potential role for YC-1 as a
novel modulator of the NO-sGC pathway in brain.
Soluble guanylyl cyclase is a heterodimeric enzyme comprising an 
and a 
subunit (Garbers,
1979). Nitric oxide regulates sGC by binding to a heme prosthetic
group (Ignarro et al., 1982;
Martin et al., 2000). Under
resting conditions, the iron in the heme of sGC is five-coordinated.
Specifically, the iron binds to the four nitrogens in the center of the heme
ring and also has a histidine group from the subunit of sGC as the
axial ligand (Fig. 1). Binding
of NO at the opposite pole of the heme iron ruptures the histidine-to-iron
bond (Fig. 1). This leads to an
allosteric change in the sGC that increases the enzyme's specific activity to
produce cGMP by more than 100-fold
(Ignarro et al., 1984). Many
vasodilator drugs activate sGC through a similar mechanism. The dramatic
coronary artery relaxing actions of nitroglycerin and nitroprusside that
relieve angina are explained by the metabolism of these
"nitrovasodilator" drugs to NO.
|
A new mechanism of sGC regulation, however, explains the actions of YC-1, a
benzylindazole derivative (Ko et al.,
1994). YC-1 was first identified as an inhibitor of platelet
aggregation, and subsequent studies showed that activation of sGC by YC-1
explains its antiplatelet activity (Ko et
al., 1994). However, unlike other sGC activators, YC-1 does not
contain NO. Instead, YC-1 exerts a distinct allosteric regulation of sGC that
can increase the activity of the purified enzyme by at least 10-fold. The
binding site for YC-1 remains unknown but it does not directly interact with
the heme iron (Friebe et al.,
1996).
The actions of YC-1 in vivo are more complex, in that its effects on sGC
synergize with those of NO (Hoenicka et
al., 1999). The presence of YC-1 makes NO a far more potent
activator of sGC, such that the enzyme can be maximally activated by the low
amounts of NO that form endogenously. This property of YC-1 may explain why
Chien et al. (2003) found, in
drug-treated brain tissue, that moderate rates of neuronal firing induced
maximal amounts of synaptic plasticity. This sensitizing action is explained
by YC-1 preventing release of NO from sGC
(Fig. 1). Under normal
conditions, the release of NO from sGC (and associated enzyme deactivation)
has a half-life of 
4 s; this is increased to more than 10 min in the
presence of YC-1 (Russwurm et al.,
2002).
Even more dramatic is the interaction of YC-1 with carbon monoxide (CO)
(Friebe et al., 1996), the
other endogenous gaseous regulator of sGC
(Verma et al., 1993). Although
heme oxygenase produces endogenous CO in neurons and in other cells,
physiological levels of CO only modestly increase sGC activity (4-fold
stimulation). Carbon monoxide does not dramatically activate purified sGC
because CO binding to the heme iron does not break the histidine-to-iron bond
necessary for allosteric regulation (Fig.
1). However, in the presence of YC-1, CO binding does rupture the
histidine-to-iron bond, and this activates sGC enzyme activity to the same
level as does NO binding (Makino et al.,
2003). Although Chien et al.
(2003) found that endogenous NO
(rather than CO) works together with YC-1 to augment hippocampal LTP, it is
possible that CO conspires with YC-1 in other brain regions or tissues.
Whether an endogenous YC-1–like molecule might regulate sGC to make the
enzyme a potent CO sensor also remains uncertain.
In addition to facilitating physiological studies of the NO-sGC pathway,
YC-1–like drugs have the potential to serve as novel therapeutics. The
vasodilator actions of YC-1 suggest possible roles in treatment of
hypertension. In fact, BAY 41-2272, a more potent compound that acts like
YC-1, lowered blood pressure and decreased mortality in a rat model of
hypertension (Stasch et al.,
2001). Furthermore, these compounds may also be beneficial in
treatment of male erectile dysfunction, because YC-1 and a related compound,
A-350619, promote penile erection in rats
(Miller et al., 2003).
Finally, by enhancing synaptic plasticity, these drugs could improve cognitive
performance or have other roles in neurological disorders. Future studies of
YC-1 and related drugs will clarify the utility of this novel class of sGC
regulators in treatment of a variety of disorders associated with deficient NO
signaling.
 |
Footnotes |
|---|
Address correspondence to: Dr. David S. Bredt, Department of Physiology, University of California at San Francisco School of Medicine, 513 Parnassus Ave., San Francisco, CA. E-mail: bredt{at}phy.ucsf.edu
|
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