Neuromedin U

Last updated
Neuromedin U
Identifiers
SymbolNMU
NCBI gene 10874
HGNC 7859
OMIM 605103
RefSeq NM_006681
UniProt P48645
Other data
Locus Chr. 4 q12
Search for
Structures Swiss-model
Domains InterPro

Neuromedin U (NmU or NMU) is a neuropeptide 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, pain perception, appetite, bone growth, and hormone release. It was first isolated from the spinal cord in 1985, and named after its ability to cause smooth muscle contraction in the uterus. [1] [2] [3] [4] [5] [6] [7] [8]

Contents

Structure

Neuromedin U is a highly conserved neuropeptide present in many species, existing as multiple isoforms. For example, in humans it is a 25 amino acid peptide (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 region of the entire peptide. [9] 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: YKVNEYQGPVAPSGGFFLFRPRN-(NH2). [1]

Function

The activation of NmU receptors leads to intracellular signal transduction via calcium mobilization, phosphoinositide (or PI) signaling, and the inhibition of cAMP production [10]

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. [11] i.c.v administration of NmU elevates the plasma 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 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 distributional 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 [11]

Role in disease

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, it induces c-Met, a proto-oncogene that encodes the mesenchymal-epithelial transition factor (MET) protein. Increased invasiveness as well as an increased hepatocyte growth factor (HGF)-mediated scattering suggest NmU is also involved in the HGF-c-Met paracrine loop regulating cell migration. [10]

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 (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 test. Furthermore, facilitated excitatory synaptic transmission 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 (CRH), suggests an alternative role in mediating stress response. NmU and its receptors are also abundantly expressed in nociceptive sensory pathways, including the dorsal root ganglia (DRG), spinal cord, and brainstem. In particular, NmU induces hyperalgesia, allodynia, 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 levels of corticosterone, and stimulates the release of CRH from hypothalamic explants in vitro . Central administration of NmU also induces expression of key genes in hypothalamic areas associated with stress, as well as stress-related behaviours that can be blocked by CRH antagonist (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. [9]

See also

Related Research Articles

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The paraventricular nucleus is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller amount of vasopressin, otherwise the nucleus also secretes corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). CRH and TRH are secreted into the hypophyseal portal system and act on different targets neurons in the anterior pituitary. PVN is thought to mediate many diverse functions through these different hormones, including osmoregulation, appetite, and the response of the body to stress.

Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neoendorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” “Big Dynorphin” is a 32-amino acid molecule consisting of both dynorphin A and dynorphin B.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

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<span class="mw-page-title-main">Neuropeptide Y</span> Mammalian protein found in Homo sapiens

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β-Endorphin Peptide hormone in humans

β-Endorphin (beta-endorphin) is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.

<span class="mw-page-title-main">Calcitonin gene-related peptide</span> Peptide hormone in animals

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha, and CGRP beta. α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).

<span class="mw-page-title-main">Neurotensin</span> Chemical compound

Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthetized rats.

<span class="mw-page-title-main">Galanin</span>

Galanin is a neuropeptide encoded by the GAL gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.

<span class="mw-page-title-main">Lateral hypothalamus</span>

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

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<span class="mw-page-title-main">Neurokinin A</span> Chemical compound

Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.

<span class="mw-page-title-main">Neuromedin N</span> Chemical compound

Neuromedin N is a neuropeptide derived from the same precursor polypeptide as neurotensin, and with similar but subtly distinct expression and effects. Composed of the amino acid sequence Lys-Ile-Pro-Tyr-Ile-Leu, neuromedin N is homologous to neurotensin, both of whose sequences are found on the pro neurotensin/neuromedin N precursor C-terminus. Both sequences of neuromedin N as well as neurotensin are flanked by Lys-Arg amino acids, which comprise a consensus sequence for the endoprotease proprotein convertase. Neuromedin N is primarily synthesized in the neural and intestinal tissues of mammals; in studies performed in mice, neuromedin N's physiological effects were shown to include hypothermia and analgesia, arising from the peptide's ligand association to and interaction with neurotensin type 2 (NTS2) G protein-coupled receptors.

<span class="mw-page-title-main">Urotensin-II receptor</span> Protein-coding gene in the species Homo sapiens

The urotensin-2 receptor (UR-II-R) also known as GPR14 is a class A rhodopsin family G protein coupled-receptor (GPCR) that is 386 amino acids long which binds primarily to the neuropeptide urotensin II.[1] The receptor quickly rose to prominence when it was found that when activated by urotensin II it induced the most potent vasoconstriction effect ever seen. While the precise function of the urotensin II receptor is not fully known it has been linked to cardiovascular effects, stress, and REM sleep.

The neuromedin U receptors are two G-protein coupled receptors which bind the neuropeptide hormones neuromedin U and neuromedin S. There are two subtypes of the neuromedin U receptor, each encoded by a separate gene.

<span class="mw-page-title-main">Corticotropin-releasing hormone receptor 1</span> Protein and coding gene in humans

Corticotropin-releasing hormone receptor 1 (CRHR1) is a protein, also known as CRF1, with the latter (CRF1) now being the IUPHAR-recommended name. In humans, CRF1 is encoded by the CRHR1 gene at region 17q21.31, beside micrototubule-associated protein tau MAPT.

<span class="mw-page-title-main">Antalarmin</span> Chemical compound

Antalarmin (CP-156,181) is a drug that acts as a CRH1 antagonist.

Neuromedin S is a 36-amino acid neuropeptide found in the brain of humans and other mammals. It is produced in the suprachiasmatic nucleus of the hypothalamus and is related to neuromedin U. It is thought to be involved in regulation of circadian rhythm and also has appetite suppressant effects, as well as regulating the release of several other peptide hormones including vasopressin, luteinizing hormone, and oxytocin.

<span class="mw-page-title-main">Central nucleus of the amygdala</span> Nucleus within the amygdala

The central nucleus of the amygdala is a nucleus within the amygdala. It "serves as the major output nucleus of the amygdala and participates in receiving and processing pain information."

References

  1. 1 2 Brighton PJ, Szekeres PG, Willars GB (2004). "Neuromedin U and its receptors: structure, function, and physiological roles". Pharmacol. Rev. 56 (2): 231–48. doi:10.1124/pr.56.2.3. PMID   15169928. S2CID   884735.
  2. ↑ Torres R, Croll SD, Vercollone J, Reinhardt J, Griffiths J, Zabski S, Anderson KD, Adams NC, Gowen L, Sleeman MW, Valenzuela DM, Wiegand SJ, Yancopoulos GD, Murphy AJ (August 2007). "Mice genetically deficient in neuromedin U receptor 2, but not neuromedin U receptor 1, have impaired nociceptive responses". Pain. 130 (3): 267–78. doi:10.1016/j.pain.2007.01.036. PMID   17379411. S2CID   23617159.
  3. ↑ Novak CM, Zhang M, Levine JA (September 2007). "Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity". Brain Research. 1169: 57–68. doi:10.1016/j.brainres.2007.06.055. PMC   2735201 . PMID   17706946.
  4. ↑ Vigo E, Roa J, Pineda R, Castellano JM, Navarro VM, Aguilar E, Pinilla L, Tena-Sempere M (November 2007). "Novel role of the anorexigenic peptide neuromedin U in the control of LH secretion and its regulation by gonadal hormones and photoperiod". American Journal of Physiology. Endocrinology and Metabolism. 293 (5): E1265–73. doi:10.1152/ajpendo.00425.2007. PMID   17726140.
  5. ↑ Iwai T, Iinuma Y, Kodani R, Oka J (May 2008). "Neuromedin U inhibits inflammation-mediated memory impairment and neuronal cell-death in rodents". Neuroscience Research. 61 (1): 113–9. doi:10.1016/j.neures.2008.01.018. PMID   18336945. S2CID   25260405.
  6. ↑ Brighton PJ, Wise A, Dass NB, Willars GB (April 2008). "Paradoxical behavior of neuromedin U in isolated smooth muscle cells and intact tissue". The Journal of Pharmacology and Experimental Therapeutics. 325 (1): 154–64. doi:10.1124/jpet.107.132803. PMID   18180374. S2CID   33931881.
  7. ↑ Tanida M, Satomi J, Shen J, Nagai K (February 2009). "Autonomic and cardiovascular effects of central neuromedin U in rats". Physiology & Behavior. 96 (2): 282–8. doi:10.1016/j.physbeh.2008.10.008. PMID   18977236. S2CID   38382442.
  8. ↑ Mitchell JD, Maguire JJ, Kuc RE, Davenport AP (February 2009). "Expression and vasoconstrictor function of anorexigenic peptides neuromedin U-25 and S in the human cardiovascular system". Cardiovascular Research. 81 (2): 353–61. doi: 10.1093/cvr/cvn302 . PMID   18987052.
  9. 1 2 Zeng H, Gragerov A, Hohmann JG, Pavlova MN, Schimpf BA, Xu H, Wu LJ, Toyoda H, Zhao MG, Rohde AD, Gragerova G, Onrust R, Bergmann JE, Zhuo M, Gaitanaris GA (December 2006). "Neuromedin U Receptor 2-Deficient Mice Display Differential Responses in Sensory Perception, Stress, and Feeding". Mol. Cell. Biol. 26 (24): 9352–63. doi:10.1128/MCB.01148-06. PMC   1698522 . PMID   17030627.
  10. 1 2 Ketterer K, Kong B, Frank D, Giese NA, Bauer A, Hoheisel J, Korc M, Kleeff J, Michalski CW, Friess H (May 2009). "Neuromedin U is overexpressed in pancreatic cancer and increases invasiveness via the hepatocyte growth factor c-Met pathway". Cancer Letters. 277 (1): 72–81. doi:10.1016/j.canlet.2008.11.028. PMID   19118941.
  11. 1 2 Brighton PJ, Szekeres PG, Wise A, Willars GB (December 2004). "Signaling and ligand binding by recombinant neuromedin U receptors: evidence for dual coupling to Galphaq/11 and Galphai and an irreversible ligand-receptor interaction". Molecular Pharmacology. 66 (6): 1544–56. doi:10.1124/mol.104.002337. PMID   15331768. S2CID   25349752.
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