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Role of Neuromedins in Pain and Signal Transduction Pathways

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Abstract

Neuromedins are a family of structurally highly conserved peptides which is initially isolated from porcine spinal cord. It is best known for their contractile activity to induce uterine smooth muscle contractionon. It is ubiquitously distributed with highest levels found in several different tissues and have been ascribed numerous functions. Amino acid alignment of the C terminus of NMU shows its structure are important for bioactivity. NmU has been isolated and sequenced from several species, particularly in mammals such as pig, rat, rabbit, dog, guinea pig, human, but also in amphibian, avian, and fish species. Two G-protein-coupled receptors for NmU have recently been detected. NMU1R, is mian expressed in peripheral tissues whereas NMU2R is expressed in the central nervous system. Here we demonstrate a role of NmU in pain, signal transduction pathways, the relationship between ion channel and nociception. It is comfirmed that NmU prevents inflammation-induced amnesia and neuronal cell-death. Moreover, intrathecal administration of NMU induced a significant enhancement of the excitability of flexor reflex in response to touch and noxious pinch. NmU cause Ca2+ influx which contributes to pacemaking activity, action potential burst firing, andbnpain transmission by T-channels. Previous study discovered the function of NMU in regulation of IA in mouse small DRG neurons. Although the potential for NmU as a novel therapeutic indications is obvious, these findings provide a molecular basis for the biochemical roles of NMU.

Key words: Neuromedin U, Neuromedin U Receptor, Ion channel, pain

The neuropeptide neuromedin U was initially isolated from porcine spinal cord, it has since been isolated and sequenced from several species, particularly in mammals such as pig, rat, rabbit, dog, guinea pig, human, but also in amphibian, avian, and fish species. The sequence of NMU is highly conserved, this means that NMU is ancient and plays an important biological role. NmU involvement in key processes suggests the possibility that this neuropeptide could be a relevant therapeutic target in nociception and inflammation.

Structure

The amino acid sequences of these are usually 8 or 25 amino acids long, named NmU-8 and NmU-25 respectively.In the previous study, other forms were also found such as NMU-17, NMU-23. NmU is synthesized as a amino acid precursor containing the NmU peptide within the C terminus. NmU precursors have several characteristics affiliated with the precursors of small regulatory peptides. These precursors are cleaved by proteases which are unknown. Moreover, the C-terminal pentapeptide (Phe-Arg-Pro-Arg-Asn-NH 2 ) is same in all species, although in mammalian species, the C-terminal heptapeptide (Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH 2) is thoroughly conserved. The C terminus of amino acid is so conservative that NmU structure closely correlates with its function. N-terminal region also changes NmU function, although these modifications appear to be related to potency and stability of the molecule.

Distribution of Neuromedin U

The application of chromatographic and immunological techniques, particularly radioimmunoassay (RIA) and immunocytochemistry (ICC) contribute much to our finding of the widespread distribution of NmU. The localisation and molecular nature of NmU-like immunoreactivity (NmU-LI) can be detected by radioimmunoassay, immunocytochemistry and chromatographic analysis. Recently, localization of NmU to areas, Neuromedin U-like immunoreactive structures, and subcellular structures have been express. The highest concentrations of NmU-LI can be found in the anterior pituitary and gastrointestinal tract, whereas significant levels are also found in the brain, spinal cord, and both the male and female genitourinary tract. In spinal cord levels are greater in dorsal horn than in ventral horn showing a sensory role.

Expression was found in several regions of the rat brain. In the central nervous system, neuromedin U immunoreactivity was localized to fibres which were widespread throughout the brain, except in the cerebellum. Moderate levels of the expression were detected in the pituitary gland, striatum, hypothalamus, medulla oblongata, and low to moderate levels of expression was found in hypothalamus, locus coruleus, thalamus, medulla oblongata, and substantia nigra. NmU expression in the brain may be related to regions implicated in somatosensory, motor, and auditory functions.

Moreover, The concentrations of neuromedin U-like immunoreactivity in the dorsal horn surpassed those of the ventral horn in each segment. NMU plays a strongly possible sensory role. Because in the dorsal root ganglia, high concentrations also present.

In addition, Within the genitourinary tract, high concentrations of neuromedin U-like immunoreactivity was found in the ureter, vas deferens, fallopian tube and urethra.Circulating NmU like immunoreactivity (NmU-LIR) has not been detected suggesting NmU acts more as a neuropeptide or neuromodulator than a circulating hormone.

Substance P, neuropeptide Y, vasoactive intestinal peptide and calbindin was found colocalization of neuromedin U immunoreactivity with immunoreactivity.Dotblot analyses or quantitative RT-PCR of mRNA for NmU or its precursor in both rat and human tissues can support these expression patterns of NmU-LIR.

NMU receptors

Two different G-protein-coupled receptors were identified as receptors for the neuromedin U, termed NMUR1 (also known as GPR66 and FM-3) and NMUR2 (also known as TGR-1 and FM-4). NMU1R, is mian expressed in peripheral tissues whereas NMU2R is expressed in the central nervous system. NMUR1 and NMUR2 have highly conserved C terminus which contribute to biological activility.

The human NMU1 gene maps to SHGC-33253, which is localized to chromosome 2q34-q37.NMU2 maps to SHGC-8848, which is localized to chromosome 5q31.1-q31.3

Tissue Expression Pattern of NMU1 and NMU2 RNA

Human NMUR1 mRNA was observed mostly in gastrointestinal system mostly. It is also present in the pancreas, adrenal cortex, heart, lung, trachea, mammary gland, bone marrow, peripheral blood leukocytes (particularly T cells and NK cells), genitourinary system, placenta, mammary gland, spleen, and adipose tissue. The mRNA for NMU receptor 1 was also observed in a subpopulation of small diameter neurons of dorsal root ganglion. Some studies have also detected low concentrations of NMUR1 expression in small intestine and lung, femur. NMUR1, but notNMUR2 was endogenously expressed in mouse small DRG neurons.

In humans, the expression of NMUR2 is confined mainly to discrete regions within the brain, particularly in the substantia nigra, medulla oblongata, pontine reticular formation, spinal cord, thalamus and testes. in the hippocampus, hypothalamus, and cerebral cortex, Moderate levels are also observed as with NMUR1, NMUR2 expression has been observed in peripheral tissues such as testis, gastrointestinal and genitourinary tract, liver, pancreas, adrenal gland, thyroid gland, lung,trachea, spleen, and thymus.

A variety of experimental results support the identification of NMU1 and NMU2 as functional receptors for the neuropeptide NMU. NMUR1 was observed that it was stimulated by NmU, causing the mobilization of intracellular calcium. Other study found NmU binding is high affinity and that it binds essentially irreversibly under physiological conditions and that this binding is followed rapidly by internalization.

Regulation of cellular signaling pathways by neuromedin U

NmU binding to NMUR1 and NMUR2 cause Ca2+ influx. In contrast to the Gq signals mainly conducted by NMUR1, NMUR2 routed preferentially to the Gi pathways.For NMUR1, this has been shown to be associated with phospholipase C activation. This suggests that this receptor is coupled to G proteins of the Gq/11 subfamily and Gα subunits. the influx of Ca2+and the release of arachidonic acid metabolite are most likely through a Ca2+-dependent activation of phospholipase A2. We have recently confirmed a second messenger pathway initiated NMUR1 couples sequentially to the βγ subunits of the Go protein, PKA, ERK in regulation of IA in mouse small DRG neurons. However NMUR1 couples sequentially to the α subunits of the Gi/o proteins, PKA, in regulation of T-type Ca2+ channels in mouse small DRG neurons.

Compared to Ca2+ and phosphoinositide signaling, coupling of these receptors to signal transduction pathways is less clear.

Slight inhibition of forskolin-stimulated cAMP production was detected in CHO cells treated with neuromedin U, but on either the basal or forskolin-stimulated levels of cAMP activation of hNmU-R1 which was transiently expressed in HEK293 cells has no affect.

Using the directly assessing the coupling of G proteins We also show that the activation of these pathways is the result of the dual coupling to both Gαq/11 and G αi G proteins not Gαs‚ We have also demonstrated that both hNmU-R1 and R2 activate MAP kinase.

IA palys an important role in determining the electrical functions of DRG neurons, the neuronal excitability and subsequent transmission of the nociceptive electrical signals will be regulated by IA. Previous study discovered the function of NMU in regulation of IA in mouse small DRG neurons. As same as said before, NmU binding to NMUR1 and NMUR2 cause Ca2+ influx. Ca2+ influx contributes to pacemaking activity, action potential burst firing, and bnpain transmission by T-channels. In mouse small DRG neurons NMU was found to inhibite T-currents in a dose-dependent manner. Moreover, NMU can increase the frequency of mEPSC,then lead to an increase in excitability of the postsynaptic neurones in the dorsal horn.

As described previously,the cellular signaling pathways was adjusted by NMUR1 and NMUR2.However,differential expression of ion channels contributes functional diversity to sensory neuron signaling.

NmU and NmUR1, NmUR2 are expressed in the spinal cord region associated with sensory function. In vitro experiments showed an increase in excitability of the sensory neuron in the dorsal horn. Intrathecal administration of NmU to rats and mice experience hyperalgesia and reduced pain thresholds. However, NMU KO mice showed decreased response to thermal change or immobilization stress. Further studies are required to clarify the nociceptive signaling of action of NMU.

NMUR2 maybe play a more significant role in Nociceptive effects. Because NmU facilitated excitatory synaptic transmission in spinal dorsal horn neurons, a mechanism by which stimulates pain, was not happened in spina lcord slices from NmuR2 KO mice. Moreover, the lack of this receptor in mice reduced nociceptive responses to NmU administration, such as reduced responses to pain on hot plate and formalin tests. On the contrary, Nmur1 KO mice did not show any difference in pain response compared to their wild-type littermates, suggesting that this receptor is dispensable for nociceptive signaling mediated by NmU.

In addintion, it is comfirmed that NmU prevents inflammation-induced amnesia and neuronal cell-death. Moreover, intrathecal administration of NMU induced a significant enhancement of the excitability of flexor reflex in response to touch and noxious pinch. Similarly in mice, NMU administration decreased thermal withdrawal latencies and produced a morphine-sensitive behavioral response. It is suggested that these receptors and NMU peptide may play a role in nociception because the restricted distribution of NMU receptors to a region of the spinal cord involved in nociception.

NMU also plays an important role in mast cell-mediated inflammation. It is reported NMU-R1 was highly expressed in primary mast cells, and NMU induced Ca2+ mobilization and degranulation in peritoneal mast cells. NMU can induce mast cell–mediated inflammation.

Antagonists of NmU receptors may be a treatment of neuropathic pain which are challenging to treat. Neuropathic pain is a frequent problem in many peripheral and CNS diseases from a lesion or disease affecting the somatosensory system. However, the mechanisms of neuropathic pain is incomplete. Injured peripheral nerve fibers give rise to an intense and, in some cases, also to secondary changes in dorsal horn neuronal excitability. NmU acts as a novel physiological regulator and processing, NMU receptors may prove an effective target for the treatment of neuropathic pain.


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