Tài liệu Báo cáo khoa học: From heart to mind The urotensin II system and its evolving neurophysiological role ppt

MINIREVIEW
From heart to mind
The urotensin II system and its evolving neurophysiological role
Hans-Peter Nothacker
1
and Stewart Clark
2
1 Department of Pharmacology, University of California, Irvine, CA, USA
2 The Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Introduction
Urotensin II (UII) is a peptide structurally related to
somatostatin ⁄ cortistatin peptides. It contains a carboxy-
terminal cysteine-bridged cyclic hexapeptide sequence
that is conserved across species. UII was originally iso-
lated from fish urophysis, a neuroendocrine gland
located in the caudal part of the spinal cord, using a
trout hindgut contraction assay [1]. For the decade fol-
lowing its discovery UII was regarded as an exclusive
product of the teleost urophysis. Contrary to this
belief, UII peptides have been shown to have a wide
phylogenetic distribution across the vertebrate lineage
(reviewed in [2]) and independent reports touting UII’s
potent cardiovascular effects in rats have dispelled its
mammalian irrelevance [3,4]. These important studies
inferred for the first time that a specific mammalian
UII receptor must exist and hence postulated the exist-
ence of mammalian UII-like peptides. The genes for
the mammalian orthologues coding for the preproform
of UII were finally discovered in 1998 [5,6]. Shortly
after, in the race for the identification of natural lig-
ands for orphan G-protein coupled receptors (GPCRs)

several groups including ours reported the identifica-
tion of the UII receptor, an orphan receptor known
before as both GPR14 or SENR (for sensory epithe-
lium neuropeptides-like receptor) [7–12]. When the UII
receptor was identified in 1999, all of the immediate
research was concentrated on the elucidation of
UII’s vasomodulatory properties. Indeed, the research
Keywords
acetylcholine; laterodorsal tegmental
nucleus; pedunculopontine tegmental
nucleus; REM sleep; urotensin receptors;
urotensin II; urotensin II-related peptide
Correspondence
H P. Nothacker, Department of
Pharmacology, University of California, 354
MedSurge II, Irvine CA 92697-4625, USA
Fax: +1 949 824 4855
Tel: +1 949 824 1892
E-mail:
(Received 21 June 2005, accepted 22
August 2005)
doi:10.1111/j.1742-4658.2005.04983.x
The discovery of novel biologically active peptides has led to an explosion
in our understanding of the molecular mechanisms that underlie the regula-
tion of sleep and wakefulness. Urotensin II (UII), a peptide originally
isolated from fish and known for its strong cardiovascular effects in
mammals, is another surprising candidate in the regulatory network of
sleep. The UII receptor was found to be expressed by cholinergic neurons
of laterodorsal and pedunculopontine tegmental nuclei, an area known to
be of utmost importance for the on- and offset of rapid eye movement

(REM) sleep. Recently, physiological data have provided further evidence
that UII is indeed a modulator of REM sleep. The peptide directly excites
cholinergic mesopontine neurons and increases the rate of REM sleep epi-
sodes. These new results and its emerging behavioral effects establish UII
as a neurotransmitter ⁄ neuromodulator in mammals and should spark fur-
ther interest into the neurobiological role of the peptide.
Abbreviations
CNS, central nervous system; CRF, corticotrophin-releasing factor; ERK, extracellular signal regulated kinase; GPCR, G-protein coupled
receptor; icv, intracerebroventricular; LDT, laterodorsal tegmental nucleus; PC, pro-hormone convertase; PLC, phospholipase C; PKC, protein
kinase C; PPT, pedunculopontine tegmental nucleus; PVN, hypothalamic paraventricular nucleus; REM, rapid eye movement; SENR, sensory
epithelium neuropeptides-like receptor; UII, urotensin II; URP, urotensin II-related peptide.
5694 FEBS Journal 272 (2005) 5694–5702 ª 2005 FEBS
direction was warranted by mounting evidence for a
role of UII in the pathogenesis of cardiac, renal
and hepatic disease (reviewed in [13–16]). In the fervor
of cardiovascular research successes it seemed to be
forgotten that UII was originally identified as a neuro-
peptide and that its major expression sites in mammals
were confined to certain motor nuclei of the central
nervous system (CNS). From the very beginning, these
findings pointed to a possible neuromodulatory role
for UII.
The aim of this review is to provide an overview of
the UII system and to describe the recently accumu-
lated evidence of its association with centrally acting
functions in mammals, particularly with regard to
arousal and sleep.
Molecular constituents of the UII
system
Presently, three molecules are known to form the UII

system: the UII receptor and the peptides UII and uro-
tensin-related peptide (URP). In humans, both pep-
tides are biologically synthesized from their own
respective 124 and 119 amino acid long secretory pre-
proforms that are encoded by distinct genes (Fig. 1),
located on chromosome 1 and 3, respectively. Al-
though both peptides share a considerable amount of
identity, the precursor molecules differ substantially in
their amino acid sequence. The gene structures, how-
ever, have many structural features in parallel, such as
the number of exons and placement of the active
peptide sequence at the very C-terminal end. These
conserved features greatly suggest that both have ori-
ginated from a common ancestral protein through gene
duplication and therefore should be considered para-
logue genes.
The precursors are proteolytically cleaved to pro-
duce the mature form of the biologically active pep-
tides (Fig. 1). UII’s length is heterogenous between
different species and ranges from 11 amino acids for
human to 14 amino acids for rat. This is probably due
to the lack of a highly conserved cleavage site for pro-
hormone convertase (PC) enzymes in the upstream
region of the mature peptide. This raises the possibility
of generating peptides of multiple lengths using atyp-
ical processing. On the other hand, the active peptide
of the URP precursor is amino terminally flanked by a
dibasic processing site and can be processed by typical
PC cleavage, thus generating a cysteine bridged octa-
peptide whose entire sequence is found invariant in all

mammals sequenced to date [17].
The major biologically active part of both molecules
consists of a canonical cysteine bridged hexapeptide
ring with the sequence CFWKYC, also known as core,
which is invariant between species and ⁄ or paralogues.
Destruction of the cysteine bond by covalent modifica-
tion leads to an immediate loss of biological activity
[18]. Conversely, the amino terminus of both UII and
URP from mammals does not seem to carry much bio-
logical information, as it can be chemically modified
without significant loss of activity [19,20]. It is worth-
while to mention that most of the mature mammalian
UII structures have been deduced from genomic
sequences and so far only pig UII and rat URP have
been isolated and directly sequenced from hypothala-
mus and whole brain, respectively [9,17].
All UII isoforms identified so far contain an acidic
amino acid residue (aspartic or glutamic acid) that
directly precedes its cyclic core structure (Fig. 1) [2].
This particular amino acid is absent in URP, but the
peptide is still a potent agonist at the UII receptor
with a pharmacological profile equal to that of UII
[17,20]. Therefore, this residue is not necessary for
receptor activation. However, its stringent evolutionary
conservation in all known UII isoforms implicates a
not yet understood biological function related to this
residue. It can be speculated that a receptor subtype
exists that is able to distinguish between UII and URP
peptides, but in mammalian genomes no homologous
sequences can be found that would clearly provide evi-

dence for a putative UII receptor subtype. Pharmaco-
logically, there is, so far, no indication of the existence
of a UII receptor subtype, but the possibility can not
yet be ruled out. The emergence of a UII receptor
Fig. 1. Molecular constituents of the urotensin II system. Two pep-
tides, urotensin II and urotensin II-related peptide (URP) are highly
potent agonists at the G-protein coupled urotensin II receptor and
both are thought to represent the endogenous ligands. Both pep-
tides exhibit similar pharmacological profiles but are differentially
expressed throughout the body. They share considerable similarit-
ies in their amino acid sequences, but are biosynthesized from dis-
tinct peptide precursors that are encoded by different genes. Black
amino acids in bold indicate proteolytic processing sites.
H P. Nothacker and S. Clark Urotensin II and its neurophysiological role
FEBS Journal 272 (2005) 5694–5702 ª 2005 FEBS 5695
selective antagonist offer the tools to tackle this ques-
tion [16,21].
Alternatively, the presence or absence of the acidic
residue may also influence the pharmacokinetic profile
of the peptides. In rat spinal cord motor neurons UII
and URP seem to colocalize [22]. This apparent
redundancy would only make biological sense if the
peptides act on different receptor subtypes or with a
different pharmacokinetic profile.
Little is known about the actual steps in the biosyn-
thesis and degradation of the peptides. The expression
of both precursors in a wide range of tissues ranging
from cardiovascular to CNS suggests cell type specific
differences in biosynthetic pathways due to the differ-
ential expression of proteolytic enzyme in neurons,

endothelial and smooth muscle cells. Direct evidence
has been presented for a UII converting enzyme activ-
ity present in porcine renal tissue [23]. This is an
intriguing finding, as differential expression of this or
similar enzymes would have dramatic influences on
UII functional dynamics in different tissues. The pre-
sent knowledge of UII biosynthesis has been recently
reviewed [14].
The UII receptor belongs to the large family of
GPCRs. It was originally cloned by homology screen-
ing methods as an orphan receptor called GPR14 or
SENR. Human UII receptor is located on chromo-
some 17q25 as an intronless gene that codes for a 389
amino acid long polypeptide. The receptor exhibits the
prototypical GPCR serpentine structure containing
seven transmembrane domains alternately interspersed
by intra- and extracellular loops (Fig. 1). Phylogenetic
analysis of the receptor’s primary sequence shows stri-
king similarities to the somatostatin receptor family,
most notably in the transmembrane domains. The
pharmacological relatedness of somatostatin receptors
is demonstrated by the fact that the UII receptor is
activated by micromolar concentrations of somato-
statin derivatives and can be blocked by somatostatin
antagonists [8,24]. However, it is rather implausible
that somatostatin acts at UII receptor sites in vivo
under normal physiological conditions, because UII is
more than 10 000-fold more potent and acts at pico-
molar concentrations in a quasi irreversible manner.
Initially the receptor expressed in heterologous

expression systems was thought to exclusively interact
with the Ga
q11
subclass of heterotrimeric G-proteins
which leads, via activation of phospholipase C (PLC),
to a rapid and short-lasting rise in intracellular calcium
ions. Further linkage of UII receptor to PLC was pro-
vided by studies performed with isolated rabbit thor-
acic aorta strips in which UII application increased
inositol phosphates, an effect that could be blocked by
PLC inhibitors [25]. Besides the short-term effect, a
line of evidence points to additional long lasting UII-
mediated cellular changes that result in growth stimu-
lation and cellular remodeling. Those effects have been
shown to be transduced via extracellular signal regula-
ted kinase 1 ⁄ 2 (ERK1 ⁄ 2) pathways in cardiomyocytes,
and in transfected Chinese hamster ovary cells. Those
effects are independent of both calcium ions and pro-
tein kinase C (PKC), and have been suggested to occur
via transactivation of the epidermal growth factor
receptor [26]. UII activation of ERK1 ⁄ 2 pathways has
been suggested to play a role in cardiomyocytic hyper-
trophy, a cellular adaptive response that is character-
ized by an increase in cell size and protein content in
the absence of cell proliferation.
In the CNS, indirect evidence exist that UII also
activates ERK and Rho-kinase pathways. In rat, cen-
trally administered UII causes cardiovascular responses
that were attenuated by Rho and ERK-kinase inhibi-
tors [27], but the cellular targets of this effect remain

elusive. Short-term UII receptor activation examined
by Fura-2 imaging in dissociated rat spinal cord motor
neurons showed an influx of extracellular calcium via
N-type calcium channels that could be prevented by
N-type specific channel blockers [28]. Additional experi-
ments suggested an activation of the channels via
proteinase kinase A dependent phosphorylation and
no involvement of PKC in the process.
While the UII receptor was initially considered to
only couple Ga
q
proteins, the receptor seems to be
involved in an array of interactions with other signa-
ling molecules whose full spectrum remains to be
determined.
Tissue localization of UII receptor and
peptides
Early studies using hybridization techniques revealed
strong mammalian UII expression in only restricted
areas like the spinal cord, medulla oblongata and kid-
ney [6–8]. Recently, more sensitive RT-PCR techniques
have shown a more ubiquitous distribution of UII
mRNA in various tissues and blood vessels. A recent
survey of both UII and URP transcripts in rat and
human showed species specific expression patterns for
both genes [17]. The most common denominator of
UII expression in rat and human seems to be spinal
cord, which constantly exhibits highest expression
independent of the detection technique. URP is also
ubiquitously found, but in rather low expression levels

compared with UII. The exception, where URP clearly
exceeds UII expression, is found in human reproduc-
tive tissue. In rat reproductive tissue, however, UII
Urotensin II and its neurophysiological role H P. Nothacker and S. Clark
5696 FEBS Journal 272 (2005) 5694–5702 ª 2005 FEBS
exceeds URP expression pointing to species specific
differences in the expression levels of these two mole-
cules. Interestingly, URP levels in various human brain
tissues seem to be slightly higher than UII, pointing to
URP as a possible activator of central UII receptors.
URP’s role as a centrally acting ligand, at least in rats,
is supported by the fact that it is the only peptide that
can be isolated from rat brains when monitored with a
nonselective UII ⁄ URP immunoassay [17]. On the other
hand, UII has also been found and sequenced from
porcine hypothalamus and purified to advanced degree
from human spinal cord [9,29], and therefore can also
exist in neuronal tissue, at least in certain species. UII-
like immunoreactivity, which might reflect the peptide
and ⁄ or the precursor molecules, has been localized to
cholinergic neurons of rat brainstem motor nuclei [30].
These are the same motor nuclei that show strong
expression of the UII transcript, but are absent of
URP (H P. Nothacker & S.D. Clark, unpublished
results). Therefore it is very likely that both peptides
coexist in the brain, but are expressed in different
areas and at different levels to fulfil diverse neuro-
modulatory roles. It has been recently reported that
UII and URP are both expressed by spinal cord motor
neurons, although it is not yet clear if both peptides

are also colocalized in the same neurons [22].
UII receptor expression seems rather ubiquitous
when assessed with highly sensitive RT-PCR technol-
ogy. It has to be kept in mind however, that the UII
receptor might be present in microvessels of the inves-
tigated tissue and not directly expressed in the tissue
specific cell populations. That might be one explan-
ation for the sometimes controversial results using
different detection techniques that vary in their
sensitivities. For example, the UII receptor expression
in rat brain seems to be ubiquitous when assessed by
RT-PCR [31]. Those results substantially differ when
less sensitive in situ hybridization methods are used. In
the latter case UII receptor mRNA exclusively local-
izes to brainstem cholinergic neurons of the laterodor-
sal tegmental (LDT) and pedunculopontine tegmental
nuclei (PPT), and no other expression sites could be
found [32]. Further investigation of the receptors’ site
of action using in situ binding techniques revealed a
much broader expression of the receptor. However, the
binding sites matched the projection areas of the
LDT–PPT complex leading to the hypothesis that
the binding sites might represent presynaptic neuro-
nal terminals. Because cholinergic neurons of the
LDT–PPT are functionally associated with sleep and
wake states, it led to the hypothesis that UII receptor
might be involved in the regulation of sleep-wake
cycles. Functional UII receptors are also detected in
cholinergic motor neurons of the spinal cord, possibly
in the same neuronal population that expresses UII

peptide [10,28]. UII’s role in spinal cord motor neuron
physiology remains unclear, however, in frog sciatic-
sartorius nerve-muscle preparations UII has been
shown to modulate frequencies of miniature endplate
potentials [33].
In the future more in-depth anatomical studies will
be necessary by using combinations of immunohisto-
chemical and in situ hybridization techniques in order
to fully understand the extent of the UII system. The
involvement of the UII system in sleep also points to a
possible circadian regulation of the transcript and⁄ or
protein levels that may underlie the reported differ-
ences.
Neurophysiology of UII
Behavioral effects
Studying neurophysiological effects of UII is complica-
ted by the fact that intracerebroventricular injections
of UII lead to cardiovascular responses [4,27] that are
thought to be caused by a UII activated and centrally
located regulator in the brain stem [34]. In general,
central administration of UII leads to hypertensive and
tachycardic responses [27,35,36] and the hypothalamic
paraventricular (PVN) and ⁄ or arcuate nucleus have
been suggested as anatomical substrates [34]. Parvocel-
lular neurons of the PVN synthesize corticotrophin
releasing factor (CRF) [37], which had been described
50 years ago as one of the most potent secretagogues
of adrenocorticotropic hormone (ACTH) [38,39].
Ewes, centrally injected with UII, responded with
increased plasma levels of adrenocorticotropic hor-

mone and adrenalin providing the first direct evidence
for a role of UII in the activation of the hypothalamic-
pituitary axis [40] although the pathway remains
mysterious. An increase of c-fos immunoreactivity, a
general indicator of neuronal activity, could not be
found in the PVN [41] two hours after UII injections.
Because c-fos expression temporally progresses to
downstream neuronal circuitries, and the latter study
recorded only one time point, it is possible that activa-
tion of PVN neurons could have simply been missed.
In preliminary studies also carried out in rats we have
seen a significant increase of c-fos mRNA levels in
PVN 20 min after intracerebroventricular (icv) admin-
istration. The PVN plays an important role in stress
and arousal related behavioral responses (reviewed
in [42]) and several stress-related responses have
been reported in rodents after central UII injection.
Low doses of icv administered UII into rats led to a
H P. Nothacker and S. Clark Urotensin II and its neurophysiological role
FEBS Journal 272 (2005) 5694–5702 ª 2005 FEBS 5697
dose-dependent increase in locomotion in a familiar
environment and a dose-dependent increase of ambula-
tory movements, although the effects were less pro-
nounced as compared with CRF and orexin, which
are both much stronger inducers of locomotion and
arousal in rats [31].
In mice central UII injections caused anxiety-like
behavior assessed by two different paradigms: the ele-
vated plus maze and the hole-board head-dipping test
[43]. UII acted dose-dependently in an anxiogenic fash-

ion the same way as CRF, but UII effects were much
smaller and less potent. There were marked differences
between the two peptides in regards to locomotion.
CRF administration strongly inhibits locomotion in
mice, whereas, UII does not show any effects. There-
fore, UII’s behavioral profile is different from that of
CRFs and warrants further investigations.
Investigations of the central actions of UII ⁄ URP, as
possible interchangeable agonists, have only recently
begun and a clear neurophysiological role of UII has
yet to emerge. Complicating matters is that, similar to
UII’s cardiovascular action, species specific differences
exist in the UII mediated behavioral responses that
need to be diligently addressed. It also has to be kept
in mind that UII is a potent vasoconstrictor and icv
injected UII causes a significant increase in cortical
blood flow [44]. It is therefore conceivable that the
behavioral effects seen after icv administration of UII
are consequences of both its effects on cortical blood
flow and on neuronal activation. The generation of
UII receptor knockout mice has been completed, but
so far only investigated with regard to the modulation
of the cardiovascular system [45]. Once these mice are
made available by their industry-funded creators, they
will provide valuable information with regard to the
behavioral role of the UII system.
Sleep studies
Sleep is an essential part of the daily life cycle and as
important as food intake for survival. In mammals the
identification of sleep and wake is accomplished by

polysomnography, the simultaneous recording of elec-
trophysiological potentials measured in the cortex and
skeletal musculature of the neck and eye. Sleep exhibits
a distinct architecture that can be basically divided
into three different states; wakefulness, slow wave and
rapid eye movement (REM, also known as paradoxical
sleep). In most laboratory animals such as rodents the
three stages form a cycle that is repeated many times
during the entire sleep period, but occurs less fre-
quently in humans. In waking states, neurotransmitter
systems governed by norepinephrine, serotonin, and
acetylcholine are all activated in the brainstem, while
in slow wave sleep, all are suppressed. Wakefulness is
accompanied by fast, low-voltage electrical activity in
the cortex and the subcortical structures of the brain,
and by a significant amount of tonus in the skeletal
muscles. REM sleep represents a paradox sleep state in
the sense that electrical activity in the cortex is similar
to that seen in wakefulness while electrical activity in
muscles has disappeared.
REM sleep is related to the specific activation of
cholinergic circuits located in the LDT and PPT of the
pons-midbrain transition area (Fig. 2). Lesions of the
cholinergic LDT–PPT complex lead to a loss of REM
sleep without deficits in wakefulness and cortical acti-
vation [46]. The injection of cholinergic agonists into
the medial pontine reticular formation, a target region
of the LDT–PPT induces a REM-like state [47–50].
These and other studies clearly indicate that choliner-
gic neurons in the PPT are important regulators of

REM sleep (reviewed in [51]).
The expression of UII receptor mRNA in choliner-
gic LDT–PPT neurons led to the hypothesis that UII
might influence cholinergic LDT–PPT neuron activity
and alter REM sleep patterns in rats. Recent data pro-
vide evidence that UII in fact acts as a modulator of
REM sleep [44]. Local administration of UII into the
PPT led to a significant increase in the number of
REM sleep episodes and this increase could be blocked
by a UII antagonist. Wakefulness and slow wave sleep
were not significantly affected by UII indicating a
Fig. 2. Schematic drawing of a sagittal section through the rat brain
summarizing the organization of the central urotensin II system.
Red colored areas represent the locations of urotensin II receptor
binding sites, whereas, the magenta area corresponds to the major
UII receptor mRNA expression site in the PPT–LDT. The area high-
lighted in green indicates localization of UII precursor mRNA.
Arrows depict the projection fields of the PPT–LDT area that cor-
respond at large with UII receptor binding sites. UII receptors are
thought to be located at the presynaptic side of PPT–LDT termi-
nals. CPu, caudate putamen; IPN, interpeduncular nucleus; LDTg,
laterodorsal tegmental nuclei; PPTg, pedunculopontine tegmental
nuclei; VTA, ventral tegmental area.
Urotensin II and its neurophysiological role H P. Nothacker and S. Clark
5698 FEBS Journal 272 (2005) 5694–5702 ª 2005 FEBS
unique profile not seen with other sleep related pep-
tides like hypocretin ⁄ orexin that enhances wakefulness
and suppresses REM sleep [52]. Similar effects of UII
on REM sleep episodes were observed by icv route of
administration, but analysis of high-frequency electro-

encephalogram bands suggest qualitative differences in
cortical activation between the two routes of adminis-
tration. Moreover, icv administered UII also led to an
increase in cortical blood flow, which points to the direct
activation of cerebral vasculature or the activation of
brain areas that are involved in cardiovascular regula-
tion. The noradrenergic A1 area, located in the lower
medulla has been identified as a possible neural sub-
strate of UII’s central cardiovascular action because
microinjections of UII into A1 causes strong systemic
cardiovascular responses in anesthetized rats [34].
At first UII’s ability to increase the number of REM
sleep episodes may seem at odds with the earlier dis-
cussed observations, which point to more anxiogenic
and stress related properties. This apparent contradic-
tion may be due to the time course of the effect, and
the route of administration. The studies describing
increased locomotion and anxiety were measured soon
after UII application (within one hour) and utilize icv
route of administration that is known to increase corti-
cal blood flow [44] within the same period of time.
Huitron-Resendiz et al. [44], reported that when UII
was applied icv, a significant increase in wakefulness
was observed during the first hour postinjection. The
amount of wakefulness returned to control levels after
two hours, whereas, the increase in the number of
REM sleep episodes could be observed for up to five
hours. Local UII application into the PPT did not pro-
duce any effect on wakefulness, nor was there an
increase in cerebral blood flow, suggesting the effect

on wakefulness was not due to UII action on the PPT.
Therefore, the acute effects that have been measured
and interpreted as anxiogenic, or stress related, may be
due to UII induced changes in cerebral blood flow or
other cardiovascular changes that follow a more rapid
time course.
The most direct evidence for UII neuromodulatory
properties in the PPT comes from electrophysiological
studies [43]. UII evoked membrane depolarization and
promoted firing of cholinergic PPT neurons that were
identified by immunohistochemical means while neigh-
boring noncholinergic neurons were not affected. These
data show for the first time that UII is able to directly
activate central neurons and may even act as a neuro-
transmitter. Together, the results are consistent with
the idea that UII plays a role as a modulator of REM
sleep and establishes UII as neuromodulatory peptide
in addition to its well known cardiovascular properties.
To establish UII as an important player in the
modulation of cholinergic LDT–PPT neurons, one
central questions remains: where are the UII positive
neurons located that project to and activate the cho-
linergic mesopontine neurons? UII and URP are both
candidates that could pharmacologically fulfil this task
because both act with similar potencies at the UII
receptor [20,53]. Interestingly, URP seems to be the
one that exists in rat brains as a peptide, whereas, UII
can only be found in the form of mRNA transcripts
[5,17]. This suggests that URP might possibly be the
endogenous regulator of REM sleep, at least in rat.

Preliminary data collected in our laboratory from rats
show only diffuse URP mRNA expression in certain
areas of the medulla oblongata that are not known to
project to the PPT. There will be a need to produce
selective tools (antibodies, UII ⁄ URP transgenic mouse
strains) that distinguish between the two precursors
and that can be used to create a comprehensive map
of the anatomical circuitry of the UII system. An
established UII circuitry will help to build hypothetical
models that can be experimentally tested and that will
aid the understanding of UII’s interaction with other
sleep and wake promoting systems.
Conclusions
The discovery of UII as a direct activator of central
cholinergic neurons and a modulator of REM sleep
features again the power of reverse physiological strat-
egies to gain new insights into little understood physio-
logical processes. It also introduces a novel player in
the neurochemistry and the electrophysiology of the
complex basis of sleep regulation and offers the oppor-
tunity to study the UII system in relation to other
sleep associated neuropeptides. More sleep studies will
be necessary to establish UII’s role in REM sleep
modulation. Besides the sleep data, there is an accu-
mulation of evidence that the UII system might have a
general role in promoting acetylcholine release and act
as an excitatory modulator. The availability of mouse
models devoid of UII receptor or its ligands will pro-
vide a rational approach for the investigation of the
neurophysiological role of the UII system. While our

understanding of the molecular constituents of the UII
system in mammals seems to be complete, the anatom-
ical distribution of the precursors on the protein level
still remains to be established in order to understand
the interconnectivity of the UII system with other
brain circuitries. Promising UII receptor antagonists
[21] are already in early phase clinical development for
diabetic nephropathy. Depending on their pharmaco-
dynamic profiles, these antagonists could provide
H P. Nothacker and S. Clark Urotensin II and its neurophysiological role
FEBS Journal 272 (2005) 5694–5702 ª 2005 FEBS 5699
invaluable pharmacological tools to further extend
sleep studies, and will be critical in evaluating the phy-
siological effects of UII in humans.
Acknowledgements
We would like to thank our many excellent collabora-
tors who have contributed to the studies reviewed here.
The work of Hans-Peter Nothacker is supported by
Grant MH68396 of the National Institute of Mental
Health.
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