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- Review -
Molecular Yin and Yang of erectile function and dysfunction
Ching-Shwun Lin1, Zhong-Cheng
Xin2, Zhong Wang3, Guiting
Lin1, Tom F. Lue1
1Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San
Francisco, CA 94143, USA
2Andrology Center, Peking University First Hospital, Beijing 100009, China
3Department of Urology, Ninth Hospital, Shanghai Second Medical University, Shanghai 200011, China
Abstract
In regard to erectile function, Yin is flaccidity and Yang erection. In the past decade, research has mostly focused
on the Yang aspect of erectile function. However, in recent years, the Yin side is attracting increasingly greater
attention. This is due to the realization that penile flaccidity is no less important than penile erection and is actively
maintained by mechanisms that play critical roles in certain types of erectile dysfunction (ED); for example, in diabetic
patients. In addition, there is evidence that the Yin and Yang signaling pathways interact with each other during the
transition from flaccidity to erection, and vice versa. As such, it is important that we view erectile function from not
only the Yang but also the Yin side. The purpose of this article is to review recent advances in the understanding of the
molecular mechanisms that regulate the Yin and Yang of the penis. Emphasis is given to the Rho kinase signaling
pathway that regulates the Yin, and to the cyclic nucleotide signaling pathway that regulates the Yang. Discussion is
organized in such a way so as to follow the signaling cascade, that is, beginning with the extracellular signaling
molecules (e.g., norepinephrin and nitric oxide) and their receptors, converging onto the intracellular effectors (e.g.,
Rho kinase and protein kinase G), branching into secondary effectors, and finishing with contractile molecules and
phosphodiesterases. Interactions between the Yin and Yang signaling pathways are discussed as well.
(Asian J Androl 2008 May; 10: 433_440)
Keywords: erectile function; erectile dysfunction; molecular mechanisms; Rho kinase signaling; cyclic nucleotide signaling; Yin_Yang
Correspondence to: Dr Ching-Shwun Lin, Knuppe Molecular Urology Laboratory, University of California, San Francisco, CA 94143,
USA.
Tel: +1-415-476-3800 Fax: +1-415-476-3803
E-mail: clin@urology.ucsf.edu
Received 2007-12-21 Accepted 2008-01-21
DOI: 10.1111/j.1745-7262.2008.00396.x
1 Introduction
The Chinese Dau (Tao) philosophy stipulates that all things exist in two opposing yet complementary states, Yin
and Yang. Simply put, Yin is feminine, Yang masculine. And, when it comes to the penis, flaccidity is Yin and erection
Yang. In ancient Egypt, an erect penis, depicted on wall carvings in several temples, symbolizes power, fertility, and victory
(e.g.,
http://www.touregypt.net/featurestories/min.htm). In the modern day, most of us can still recall the phenomenon
that swept across the globe with the debut of Viagra (Pfizer Inc., New York, USA). So, it can be safely assumed that
having a strong Yang in the penis is a universal and timeless desire in all human races. However, the fact that every
man's penis stays most of the time in the Yin state tells us loud and clear that, no matter how hard we try, Yin will
always be the dominant force in penises. By recognizing this fact, hopefully we will all agree that, after decades of
research focusing on the Yang side, we should now take a serious look at the process in which the Yin force operates
in the penis. And, as the Yin_Yang philosophy further
proclaims, a better understanding of the Yin should lead
to a better management of the Yang.
So, what is the Yin force? Is it simply a static, sort of
lifeless, state of the penis? Or is it something active and
dynamic? Once again, just as the Yin_Yang philosophy
dictates, whether it is Yin or Yang, there is always
something going on within each state. We all know that the
cavernous smooth muscle (CSM) is contracted when the penis is flaccid. So something must be in operation
to maintain the contracted state of the CSM.
2 Yin and Yang of erectile function
Nature's many activities _ such as day and night, or
the four seasons _ go around and around like a spinning
wheel of Tai Chi. So does the erection cycle (Figure 1),
which is initiated by sexual stimulation and maintained
during continuous sexual stimulation. Erection starts to
subside at ejaculation or at the cessation of sexual
stimulation and the subsequent flaccidity state is maintained
until the next sexual stimulation or nocturnal erection.
Thus, both the erection and the flaccidity states of the
penis exist in two phases, initiation and maintenance. In
Figure 1, erection and flaccidity are equated to relaxation
and contraction, respectively, of the CSM.
Initiation of contraction begins with the release of
norepinephrin from sympathetic nerves [1].
Norepinephrin binds to adrenergic receptor in the cytoplasmic
membrane of CSM cells (CSMC) [2_6]. The adrenergic
receptor belongs to the G-protein-coupled receptor
(GPCR) family and, in its guanosine triphosphate
(GTP)-bound state, activates phospholipase C-β, which splits
phosphatidylinositol (4,5)-bisphosphate into inositol
trisphosphate (IP3) and diacylglycerol. Binding of
diacylglycerol to protein kinase C (PKC) could lead to CSM
contraction [7]; however, the detail of this pathway is not
well understood and interested readers are advised to read
a recent review by Larsson [8]. In contrast, the other
pathway that descends from IP3 has been well
characterized: binding of IP3 to its receptor,
IP3R, in the sarcoplasmic reticulum triggers the release of calcium (Ca) from
the sarcoplasmic reticulum; calcium binds to calmodulin
(CaM), which then binds to and activates myosin light
chain kinase (MLCK); MLCK phosphorylates myosin light chain (MLC), which then binds to and activates
actin, resulting in contraction (Figure 2).
Three extracellular molecules, adrenalin [1],
endothelin-1 [9_14], and angiotensin II [15_18], are primarily
responsible for the maintenance of CSM contraction.
Each of them binds to a different GPCR in the
cytoplasmic membrane, leading to the activation of guanine
exchange factor, which converts RhoA-guanosine
diphosphate (GDP) to RhoA-GTP. RhoA-GTP dissociates from
GDP dissociation inhibitor and migrates to the
cytoplasmic membrane, where it binds to and activates Rho
kinase (ROCK). ROCK phosphorylates and inactivates
myosin light chain phosphatase (MLCP), allowing MLC
to stay phosphorylated and consequently
actin-contracted. This ROCK signaling pathway (Figure 3) is responsible
for the maintenance of smooth muscle contraction [19].
The contracted state is disrupted by sexual stimulation,
which triggers the release of nitric oxide (NO) from
cavernous nerves in the penis (Figure 4) [20]. NO diffuses
into CSMC and activates soluble guanyl cyclase [21],
which then catalyzes the conversion of GTP to cyclic
guanosine monophosphate (cGMP) [22]. cGMP activates protein kinase G (PKG) [23], which in turn
phosphorylates gap junctions, potassium (K) channels, and
Ca channels [24]. Phosphorylation of the K and Ca
channels leads to an increase of potassium efflux and
reduction of Ca influx, respectively [25]. When the
cytoplasmic calcium concentration falls below 500 nmol, Ca
dissociates from CaM, which in turn dissociates from the
MLCK, thus inactivating it. With its kinase being
inactivated and its phosphates being removed by phosphatase,
the MLC becomes dephosphorylated. Dephosphorylated
MLC inhibits the binding of the myosin head to actin,
resulting in the relaxation of CSMC [26]. A more
detailed discussion of this Yang pathway can be found in
the authors' earlier review article [27].
The initial phase of smooth muscle relaxation results
in reduced peripheral resistance of cavernosal arterioles
and thereby allows blood to flow into the penis under the
driving force of systemic blood pressure. The increased
blood flow causes shear stress that causes endothelial
cells to release additional NO [28], which augments the
ongoing PKG signaling pathway. As a result, sinusoidal
spaces are filled with blood, creating a pressure to
compress the venules against the tunica albuginea, limiting
venous outflow [29]. This veno-occlusion mechanism,
together with the ongoing arterial inflow, leads to a
dramatic increase of the intracavernosal pressure and
therefore a sustained erection.
After ejaculation or discontinuation of the sexual
impulse, NO release from cavernous nerves and
endothelial cells ceases or declines, resulting in a drop of cGMP
production in CSMC. Meanwhile, the pre-existing cGMP
is hydrolyzed to guanosine monophosphate by
phosphodiesterase 5 [30], thereby depleting the cGMP store and
returning its downstream targets to the deactivated state
in CSMC. As the Yang forces retreat, the Yin forces
advance (see above), and the erection cycle is completed.
The above-described contraction/relaxation processes
are responsible for "normal" erectile function, but
alternative Yin and Yang mechanisms do exist. For example,
intracavernosal prostaglandin E (PGE) injection is one of
the most effective treatments for erectile dysfunction (ED)
[31]. However, PGE signals through the cyclic
adenosine monophosphate (cAMP), not cGMP, pathway.
Binding of PGE to its receptor, also belonging to the
GPCR family, activates adenyl cyclase, which converts
adenosine trisphosphate to cAMP [32]. Binding of cAMP
to protein kinase A results in protein kinase A activation,
which phosphorylates Ca and K channels, with subsequent events that are similar to the above-described
cGMP pathway. Another example is the identification of
natriuretic peptide receptors in CSMC [33, 34]. These
receptors are called particulate guanyl cyclase (pGC)
because they are cytoplasmic membrane-bound GC. Soluble guanyl cyclase is activated by NO (see above),
but pGC is activated by natriuretic peptides. Activated
pGC converts GTP to cGMP, which activates PKG, and
so forth, as described above for the NO_cGMP pathway.
The Yin_Yang philosophy also stipulates that Yin and
Yang are interdependent and interact with each other, or
"cross-talk", as molecular biologists would say.
Evidence for Yang intercepting the Yin pathway is presented
with the discovery that PKG phosphorylates and thereby
inhibits RhoA [35], thus suppressing the Yin forces.
However, ROCK (a Yin molecule) can inhibit both the
expression and activity of endothelial nitric oxide
synthase (eNOS; a Yang molecule) [36_38], thus
decreasing NO production.
3 Yin and Yang of ED
By far the most important concept in the Yin_Yang
philosophy is that, in order for an entity to be wholesome,
Yin and Yang must exist in balance in that entity. In fact,
traditional Chinese medicine, be it diagnostic or
therapeutic, is entirely based on this concept. So, for the penis to
be wholesome, Yin and Yang must exist in balance _ too
much Yin, one gets ED; too much Yang, priapism. ED is
known to be associated with aging and several
pathological conditions such as diabetes, hypertension,
hypogonadism, hypercholesterolemia, and prostatectomy-caused
injuries. Aging is associated with decreased neuronal
nitric oxide synthase (nNOS) expression in the corpus
cavernosum [39]. Diabetes is associated with
inactivation of eNOS [40] and decreased PKG activity [41].
Hypogonadism is perhaps associated with decreased nNOS and eNOS expression [42_44], although
contradictory findings also exist [45, 46]. Hypercholesterolemia
does affect nNOS or eNOS expression [47] but is
associated with a decreased level of phosphorylated
(functional) eNOS [48]. Finally, injury to the cavernous nerves
results in decreased nNOS expression [49, 50].
The above examples are medical conditions in which
lowered levels of Yang molecules are associated with ED,
but increased levels of Yin molecules have also been
identified in these conditions. For example, MLCP
phosphorylation is markedly increased [51], thus in favor of
contraction, in the penis of aged rats. RhoA/ROCK
activity and MLCP phosphorylation are increased in the penis
of diabetic rabbits and rats, respectively [13, 38]. RhoA
expression and RhoA/ROCK activity are increased in the
penis of hypertensive [52, 53] and castrated rats [54].
Sickle cell anemia is a well-known risk factor for
priapism [55]. The possible underlying mechanism is
that sicklemia causes tissue ischemia, which inhibits CSM
contraction [56]. In support of this hypothesis, we have
previously reported that CSMC express much lower
levels of phosphodiesterase 5 when cultured under low
oxygen (hypoxia) conditions [57]. More recently, we
discovered that hypoxia also causes lowered expression of
RhoA, ROCK, and MYPT1 (the regulatory subunit of MLCP) in CSMC and CSM
(Lin et al., unpublished data, 2007). Thus, it appears that insufficient expression of
Yin molecules is a possible cause of priapism.
4 Concluding remarks
Despite being thousands of years old, the Yin_Yang
philosophy is still applicable to modern medicine in which
all sorts of health problems are being investigated for
their underlying causes at the molecular level. Although
the penis is undoubtedly a Yang organ, it might come as
a surprise to some that it actually contains both Yin and
Yang molecules, and Yin is actually the dominant force.
Thus, it is advisable that we carry out our research by
looking not only at the Yang side but also the Yin.
Although boosting the Yang has been the preferred route to
treat ED, it is possible that reducing the Yin could work
just as well. By balancing the Yin_Yang seesaw, one
should be able to achieve the Tai Chi state of perpetual
happiness.
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