Neuromedin U is a neuropeptide

Neuropeptide

Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...

 found in the brain of humans and other mammals, which has a number of diverse functions including contraction of smooth muscle, regulation of blood pressure

Blood pressure

Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...

, pain perception, appetite, bone growth, and hormone

Hormone

A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

 release. It was first isolated from the spinal cord

Spinal cord

The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

 in 1985, and named after its ability to cause smooth muscle contraction

Muscle contraction

Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...

 in the uterus.

Structure

Neuromedin U is a highly conserved neuropetide present in many species, existing as multiple isoforms. For example, in humans it is a 25 amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 peptide

Peptide

Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 (U-25) in rats it is 23-aas long (U-23) and it has been found to be as low as 8-aas long in some mammals. NMU-8 is identical to the C terminus of NMU-25, thus is the most highly conserved

Conserved sequence

In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...

 region of the entire peptide. The relative contribution of the different isoforms to the biological function of neuromedin U is generally not well understood. Neuromedin U, like many neuroactive peptides, is amidated at the C-terminus, and all isoforms have identical C-terminal heptapeptides.

The sequence of neuromedin U-23 in rats is: YKVNEYNGPVAPSGGFFLFRPRN-(NH2).

Function

The activation of NmU receptors leads to intracellular signal transduction

Signal transduction

Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

 via calcium mobilization, phosphoinositide (or PI) signaling, and the inhibition of cAMP

Cyclic adenosine monophosphate

Cyclic adenosine monophosphate is a second messenger important in many biological processes...

 production

NmU will contract smooth muscle only in a tissue- and species-specific manner. Intracerebroventricular (or i.c.v) administration of the neuropeptide mediates stress response and increases both the arterial pressure and heart rate. i.c.v administration of NmU elevates the plamsa adrenaline levels, though has no effect on the amount of plasma noradrenaline. It has been suggested that large doses of NmU inhibits the activity of the paraventricular nucleus of hypothalamus and/or the sympathetic

Sympathetic nervous system

The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...

 preganglionic neurons, thus controlling the activity.

Regulation

Neuromedin U is mediated by two receptors, peripheral NmUR1 and central nervous system NmUR2. Both receptors are examples of Class A G-protein coupled receptors (or GPCRs) with a distinct sistributional pattern. NmUR1 is expressed predominantly in the peripheral nervous system, with highest levels in the gastrointestinal tract, whereas NmUR2 is mostly found in the central nervous system, with greatest expression in the hypothalamus, medulla, and spinal cord.

The discovery of set distribution patterns has begun to allow assignation of specific roles of the two receptor subtypes within the body. What is known for certain is that recombinant NmU receptors will increase the internal calcium concentration, signaling via the MAPK/ERK pathway

MAPK/ERK pathway

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...

Cancer

Its role in cancer is not yet fully understood, though NmU and its receptor NMUR2 have been shown to be over-expressed in human pancreatic cancers compared to normal cells. Studies also showed NmU serum levels decreased after the tumors were removed, as NmU and its receptor are localized predominantly in cancer cells. Although NmU exerts no effect on cancer cell proliferation

Cell growth

The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...

, it induces c-Met, a proto-oncogene that encodes the mesenchymal

Mesenchymal stem cell

Mesenchymal stem cells, or MSCs, are multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts , chondrocytes and adipocytes...

-epithelial

Epithelium

Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...

 transition factor (MET) protein. Increased invasiveness

Invasive

Invasive may refer to:*A military invasion*An invasive species*An invasive medical procedure*The invasively progressive spread of disease from one organ in the body to another, especially in reference to cancer...

 as well as an increased hepatocyte growth factor (HGF)-mediated scattering suggest NmU is also involved in the HGF-c-Met paracrine

Paracrine signalling

Paracrine signalling is a form of cell signalling in which the target cell is near the signal-releasing cell.-Local action:Some signalling molecules degrade very quickly, limiting the scope of their effectiveness to the immediate surroundings...

 loop regulating cell migration

Cell migration

Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...

.

Pain perception and stress response

The effect of NmU on stress and pain perception pathways has been demonstrated using mice. In contrast to NmU peptide-deficient mice, NmUR2 knockout

Gene knockout

A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...

 (KO) mice appeared normal with regard to stress, anxiety, body weight regulation, and food consumption. However, the NmUR2 KO mice exhibit reduced pain sensitivity in both hot plate test and the chronic phase of the formalin

Formaldehyde

Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...

 test. Furthermore, facilitated excitatory synaptic transmission

Neurotransmission

Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...

 in spinal dorsal horn neurons, a mechanism by which NmU stimulates pain, did not occur in NmUR2 KO mice. Both NmUR2 expression and NmU-23 binding sites are highly localized to the outer layers of the spinal dorsal horn, and administration of NmU via intracerebroventricular (ICV) injections usually increases pain sensitivity in rats and mice.

The expression of NmUR2 in the paraventricular nucleus of hypothalamus (PVN), a major site for the release of Corticotropin-releasing hormone

Corticotropin-releasing hormone

Corticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...

 (CRH), suggests an alternative role in mediating stress response. NmU and its receptors are also abundantly expressed in nociceptive

Nociception

Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...

 sensory pathways, including the dorsal root ganglia (DRG), spinal cord

Spinal cord

The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

, and brainstem. In particular, NmU induces hyperalgesia

Hyperalgesia

Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...

, allodynia

Allodynia

Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...

, and increased persistent pain after formalin injection. ICV injections of NmU in rats and mice induce behavior responses associated with activation of the nociceptive pathways, for example it will increase plasma

Blood plasma

Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 levels of corticosterone

Corticosterone

Corticosterone is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands.-Roles:In many species, including amphibians, reptiles, rodents and birds, corticosterone is a main glucocorticoid, involved in regulation of fuel, immune reactions, and stress...

, and stimulates the release of CRH from hypothalamic explants

Explant culture

In biology, explant culture is a technique used for the isolation of cells from a piece or pieces of tissue. Tissue harvested in this manner is called an explant...

 in vitro

In vitro

In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

. Central administration of NmU also induces expression of key genes

Gênes

Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...

 in hypothalamic areas associated with stress, as well as stress-related behaviours that can be blocked by CRH antagonist

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

(this is absent from CRH knockout mice).

Certain stress responses are abolished in NmU knockout mice. These results suggest that NmU significantly modulates nociceptive sensory transmission.