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

MINIREVIEW

From heart to mind

The urotensin II system and its evolving neurophysiological role

Hans-Peter Nothacker1 and Stewart Clark2

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: [email protected]

(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