PathBank

Pathway Description

Norepinephrine Neurological

Rattus norvegicus

Category:

Metabolite Pathway

Sub-Category:

Physiological

Created: 2023-09-22

Last Updated: 2024-01-21

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin ad, "near", and ren, "kidney") is more commonly used in the United Kingdom, whereas "norepinephrine" (from Ancient Greek ἐπῐ́ (epí), "upon", and νεφρός (nephrós), "kidney") is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic. The general function of norepinephrine is to mobilize the brain and body for action. Norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility. In the brain, noradrenaline is produced in nuclei that are small yet exert powerful effects on other brain areas. The most important of these nuclei is the locus coeruleus, located in the pons. Outside the brain, norepinephrine is used as a neurotransmitter by sympathetic ganglia located near the spinal cord or in the abdomen, as well as Merkel cells located in the skin. It is also released directly into the bloodstream by the adrenal glands. Regardless of how and where it is released, norepinephrine acts on target cells by binding to and activating adrenergic receptors located on the cell surface. Norepinephrine is a catecholamine and a phenethylamine. Its structure differs from that of epinephrine only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. Norepinephrine is synthesized from the amino acid tyrosine by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system. While the conversion of tyrosine to dopamine occurs predominantly in the cytoplasm, the conversion of dopamine to norepinephrine by dopamine β-monooxygenase occurs predominantly inside neurotransmitter vesicles. In mammals, norepinephrine is rapidly degraded to various metabolites. The initial step in the breakdown can be catalyzed by either of the enzymes monoamine oxidase (mainly monoamine oxidase A) or COMT. From there, the breakdown can proceed by a variety of pathways. The principal end products are either Vanillylmandelic acid or a conjugated form of MHPG, both of which are thought to be biologically inactive and are excreted in the urine.[13]

References

Norepinephrine Neurological References

Arenson EB Jr, August CS: Preliminary report: treatment of the hemolytic-uremic syndrome with aspirin and dipyridamole. J Pediatr. 1975 Jun;86(6):957-61. doi: 10.1016/s0022-3476(75)80235-6.

Pubmed: 1127537

"Norepinephrine". PubChem.

Musacchio JM (2013). "Chapter 1: Enzymes involved in the biosynthesis and degradation of catecholamines". In Iverson L (ed.). Biochemistry of Biogenic Amines. Springer. pp. 1–35. ISBN 978-1-4684-3171-1.

Griffith RK (2013). "Chapter 10: Adrenergic Receptors and Drugs Affecting Adrenergic Neurotransmission". In Lemke TL, Williams DA, Zito SW, Roche VF (eds.). Foye's Principles of Medicinal Chemistry (7th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 343. ISBN 978-1-60913-345-0.

Rang HP, Ritter JM, Flower R, Henderson G (2014). "Chapter 14: Noradrenergic transmission". Rang & Dale's Pharmacology. Elsevier Health Sciences. pp. 177–196. ISBN 978-0-7020-5497-6.

McMahon A, Geertman R, Sabban EL: Rat dopamine beta-hydroxylase: molecular cloning and characterization of the cDNA and regulation of the mRNA by reserpine. J Neurosci Res. 1990 Mar;25(3):395-404. doi: 10.1002/jnr.490250317.

Pubmed: 2325165

Oyarce AM, Steveson TC, Jin L, Eipper BA: Dopamine beta-monooxygenase signal/anchor sequence alters trafficking of peptidylglycine alpha-hydroxylating monooxygenase. J Biol Chem. 2001 Aug 31;276(35):33265-72. doi: 10.1074/jbc.M101088200. Epub 2001 Jun 19.

Pubmed: 11418593

Tanaka T, Horio Y, Taketoshi M, Imamura I, Ando-Yamamoto M, Kangawa K, Matsuo H, Kuroda M, Wada H: Molecular cloning and sequencing of a cDNA of rat dopa decarboxylase: partial amino acid homologies with other enzymes synthesizing catecholamines. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8142-6. doi: 10.1073/pnas.86.20.8142.

Pubmed: 2813383

Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.

Pubmed: 15489334

Albert VR, Lee MR, Bolden AH, Wurzburger RJ, Aguanno A: Distinct promoters direct neuronal and nonneuronal expression of rat aromatic L-amino acid decarboxylase. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12053-7. doi: 10.1073/pnas.89.24.12053.

Pubmed: 1465439

Grima B, Lamouroux A, Blanot F, Biguet NF, Mallet J: Complete coding sequence of rat tyrosine hydroxylase mRNA. Proc Natl Acad Sci U S A. 1985 Jan;82(2):617-21. doi: 10.1073/pnas.82.2.617.

Pubmed: 2857492

Haycock JW, Haycock DA: Tyrosine hydroxylase in rat brain dopaminergic nerve terminals. Multiple-site phosphorylation in vivo and in synaptosomes. J Biol Chem. 1991 Mar 25;266(9):5650-7.

Pubmed: 1672315

Bevilaqua LR, Graham ME, Dunkley PR, von Nagy-Felsobuki EI, Dickson PW: Phosphorylation of Ser(19) alters the conformation of tyrosine hydroxylase to increase the rate of phosphorylation of Ser(40). J Biol Chem. 2001 Nov 2;276(44):40411-6. doi: 10.1074/jbc.M105280200. Epub 2001 Aug 13.

Pubmed: 11502746

Chu PJ, Best PM: Molecular cloning of calcium channel alpha(2)delta-subunits from rat atria and the differential regulation of their expression by IGF-1. J Mol Cell Cardiol. 2003 Feb;35(2):207-15.

Pubmed: 12606261

Hatano S, Yamashita T, Sekiguchi A, Iwasaki Y, Nakazawa K, Sagara K, Iinuma H, Aizawa T, Fu LT: Molecular and electrophysiological differences in the L-type Ca2+ channel of the atrium and ventricle of rat hearts. Circ J. 2006 May;70(5):610-4. doi: 10.1253/circj.70.610.

Pubmed: 16636499

This pathway was propagated using PathWhiz - Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.

Propagated from SMP0122188

	Ascorbic acid
	Calcium
	Carbon dioxide
	Copper
	Dehydroascorbic acid
	Dopamine
	Fe2+
	L-Dopa
	L-Tyrosine
	Norepinephrine
	Oxygen
	Pyridoxal 5'-phosphate
	Pyrroloquinoline quinone
	Water

	Aromatic-L-amino-acid decarboxylase
	Dopamine beta-hydroxylase
	Tyrosine 3-monooxygenase
	Unknown
	Voltage-dependent calcium channel subunit alpha-2/delta-2

		Ascorbic acid
		Calcium
		Carbon dioxide
		Copper
		Dehydroascorbic acid
		Dopamine
		Fe2+
		L-Dopa
		L-Tyrosine
		Norepinephrine
		Oxygen
		Pyridoxal 5'-phosphate
		Pyrroloquinoline quinone
		Water

		Aromatic-L-amino-acid decarboxylase
		Dopamine beta-hydroxylase
		Tyrosine 3-monooxygenase
		Unknown
		Voltage-dependent calcium channel subunit alpha-2/delta-2

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Norepinephrine Neurological

Norepinephrine Neurological References