Urotensin-II (U-II) is a peptide ligand that is the strongest known

vasoconstrictor Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...

. Because of the involvement of the UII system in multiple biological systems such as the

cardiovascular The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

, nervous,

endocrine The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neur ...

, and

renal The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

, it represents a promising target for the development of new drugs. In humans, Urotensin-2 is encoded by the ''UTS2''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Discovery

U-II was initially isolated from the

neurosecretory Neurosecretion is the storage, synthesis and release of hormones from neurons. These neurohormones, produced by neurosecretory cells, are normally secreted from nerve cells in the brain that then circulate into the blood. These neurohormones are sim ...

system of the

Goby Goby is a common name for many species of small to medium sized ray-finned fish, normally with large heads and tapered bodies, which are found in marine, brackish and freshwater environments. Traditionally most of the species called gobies have b ...

fish (''

Gillichthys mirabilis The longjaw mudsucker ''Gillichthys mirabilis'' is a goby ( Gobiidae) of the Pacific Ocean coast of California and Baja California, noted for its extremely large mouth and ability to survive out of water for short periods. As the common name ...

''). For many years it was thought that U-II does not exhibit significant effects in mammalian systems; a view quickly overturned when it was demonstrated that Goby U-II produces slow relaxation of mouse anococcygeus muscle, in addition to contraction of rat artery segments. In 1998, the genes for Pre-pro U-II were found in mammals proving that the

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

U-II did exist in mammals.

Structure

The U-II gene is located on chromosome 1p36. U-II peptide length varies between species due to the specific cleaving sites located at different spots depending on the species. In humans U-II length is 11 amino acids. The peptide sequence that is needed for biological function for both U-II and urotensin II-Related Peptide (URP) is known as the core. It is hexapeptide (- CYS- TYR- LYS- TRP- PHE-CYS-), and is connected at the two ends by a

disulfide bond In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

. Also just like URP the

amino terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

can be modified without any loss in pharmacological activity suggesting that it is not needed for activation of the receptor. Unlike URP, U-II has an acidic amino acid ( Glutamic or Aspartic) that precedes the core sequence. While the amino acid is not necessary for the activation of urotensin II receptor the fact that it is conserved in different species suggests that it has a biological function that has not been discovered.

Receptor

U-II is an agonist for the urotensin-II receptor which is a

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

that primarily activates the alpha subunit Gαq11. It activates PKC which then activates PLC which increases the intercellular calcium concentration. It is found in many peripheral tissues, blood vessels, and also the

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...

cholinergic neuron A cholinergic neuron is a nerve cell which mainly uses the neurotransmitter acetylcholine (ACh) to send its messages. Many neurological systems are cholinergic. Cholinergic neurons provide the primary source of acetylcholine to the cerebral corte ...

s of the laterodorsal tegmental (LDT) and the pedunculopontine tegmental nuclei (PPT). It is also found in rat

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

Tissue localization

Pre-pro U-II in both humans and rats are primarily expressed in the motorneurons of the brainstem and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...

although it is also found in small amounts in other parts of the brain as well including the

frontal lobe The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove be ...

and the

medulla oblongata The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (invol ...

. In humans U-II

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

is also found in other peripheral tissues such as the

heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex ...

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

, and

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or '' T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders ...

Function

Central nervous system

When injected intracerebroventricularly (icv) U-II causes an increase in the

corticotropin releasing factor Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that belo ...

by activating the hypothalamic paraventricular neurons. This leads to increased plasma levels of

adrenocorticotropic Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...

hormones and adrenaline. Rats and mice exhibit many stress related behaviors when injected with U-II which were tested by the

elevated plus maze The elevated plus maze (EPM) is a test measuring anxiety in laboratory animals that usually uses Animal testing on rodents, rodents as a Drug discovery#Screening and design, screening test for putative anxiolytic or anxiogenic compounds and as a ...

which measures anxiety-like effects, and the

hole-board test The hole-board test (HBT) is an experimental method used in scientific research to measure anxiety, stress, neophilia and emotionality in animals. Because of its ability to measure multiple behaviors it is a popular test in behavioral pharmacology, ...

which measures head dipping which is also an anxiety-like behavior. U-II when injected icv in rats also leads to cardiovascular responses including raising mean arterial pressure (MAP) and causing

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

. When the

arcuate nucleus The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes seve ...

, and the paraventricular nucleus, two different areas of the brain which are known to control blood pressure were injected with U-II simultaneously they caused an increase in blood pressure. When the two areas were injected separately it was discovered that U-II affected the excitatory neurons in the paraventricular nucleus and the inhibitory neurons of the arcuate nucleus. U-II when injected icv in both rats and mice also stimulates locomotion in familiar environments. This experiment was also tested in rainbow trout ( Oncorhynchus mykiss) where a stimulatory effect was also observed.. Depression-like behavior was also observed when U-II was injected in the brain by using the

forced swim test The behavioural despair test (or Porsolt forced swimming test) is a test, centered on a rodent's response to the threat of drowning, whose result has been interpreted as measuring susceptibility to negative mood. It is commonly used to measure the ...

and the tail suspension test which are used to compare molecules that are thought to cause anti-depressive-like effects.

Orexigenic An orexigenic, or appetite stimulant, is a drug, hormone, or compound that increases appetite and may induce hyperphagia. This can be a medication or a naturally occurring neuropeptide hormone, such as ghrelin, orexin or neuropeptide Y, which i ...

behavior which is increased appetite and thirst were also observed after icv injection of U-II in rats.

Peripheral tissue effects

U-II has a variety of effects on different tissues. In blood vessels it can cause contraction. In rat pancreas U-II inhibits

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...

secretion. It also affects the kidneys including sodium transport,

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...

and

glucose metabolism Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms. Carbohydrates are central to many essential metabolic pathways. P ...

, and natriuretic effects. It has been linked to

cardiac fibrosis Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic ...

and

hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J. ...

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

, renal dysfunction, and

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...