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Pathway Description
Metoclopramide Serotonergic Smooth Muscle Contraction
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2023-09-08
Last Updated: 2023-11-27
Metoclopramide is a dopamine receptor antagonist and has been approved by the FDA to treat nausea and vomiting in patients with gastroesophageal reflux disease or diabetic gastroparesis by increasing gastric motility.. Metoclopramide works by antagonizing central and peripheral dopamine-two receptors (D2) in the medullary chemoreceptor trigger zone in the area postrema, usually stimulated by levodopa or apomorphine. It achieves this by decreasing the sensitivity of visceral afferent nerves that transmit from the gastrointestinal system to the vomiting center in the area postrema in the chemoreceptor trigger zone. In addition to antagonizing dopamine receptors, metoclopramide is an antagonist at 5HT3 (type 3 serotonin receptors) and an agonist at 5HT4 receptors. Metoclopramide's agonism of 5-HT4 receptors in the gastrointestinal tract can stimulate gastrointestinal motility, including enhancing gastric emptying and promoting peristalsis. This effect can be beneficial in conditions associated with delayed gastric emptying, such as gastroparesis, and it may help relieve symptoms like nausea and vomiting. Activation of 5-HT4 receptors can also lead to the release of acetylcholine, which further enhances smooth muscle contraction in the gut. In the gastrointestinal tract, when serotonin (5-HT) binds to 5-HT4 receptors in the GI tract, it initiates intracellular signaling through a G-protein-coupled mechanism. 5-HT4 receptors are typically coupled to Gs proteins. Activation of Gs proteins stimulates adenylate cyclase (AC), leading to increased production of cyclic AMP (cAMP) from ATP. The increase in cAMP levels activates protein kinase A (PKA) through the cAMP-PKA pathway. PKA activation can lead to smooth muscle contraction in the GI tract. This increased contractility promotes peristalsis and enhances gastric emptying by propelling food and digestive contents through the GI tract.
References
Metoclopramide Serotonergic Smooth Muscle Contraction References
Isola S, Hussain A, Dua A, Singh K, Adams N: Metoclopramide.
Pubmed: 30137802
Lee A, Kuo B: Metoclopramide in the treatment of diabetic gastroparesis. Expert Rev Endocrinol Metab. 2010;5(5):653-662. doi: 10.1586/eem.10.41.
Pubmed: 21278804
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Ramsbottom N, Hunt JN: Studies of the effect of metoclopramide and apomorphine on gastric emptying and secretion in man. Gut. 1970 Dec;11(12):989-93. doi: 10.1136/gut.11.12.989.
Pubmed: 5511820
Sanger GJ, Andrews PLR: A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research. Front Pharmacol. 2018 Sep 4;9:913. doi: 10.3389/fphar.2018.00913. eCollection 2018.
Pubmed: 30233361
Kurabayashi M, Komuro I, Tsuchimochi H, Takaku F, Yazaki Y: Molecular cloning and characterization of human atrial and ventricular myosin alkali light chain cDNA clones. J Biol Chem. 1988 Sep 25;263(27):13930-6.
Pubmed: 3417683
Hoffmann E, Shi QW, Floroff M, Mickle DA, Wu TW, Olley PM, Jackowski G: Molecular cloning and complete nucleotide sequence of a human ventricular myosin light chain 1. Nucleic Acids Res. 1988 Mar 25;16(5):2353. doi: 10.1093/nar/16.5.2353.
Pubmed: 3357795
Fodor WL, Darras B, Seharaseyon J, Falkenthal S, Francke U, Vanin EF: Human ventricular/slow twitch myosin alkali light chain gene characterization, sequence, and chromosomal location. J Biol Chem. 1989 Feb 5;264(4):2143-9.
Pubmed: 2789520
Lazar V, Garcia JG: A single human myosin light chain kinase gene (MLCK; MYLK). Genomics. 1999 Apr 15;57(2):256-67.
Pubmed: 10198165
Potier MC, Chelot E, Pekarsky Y, Gardiner K, Rossier J, Turnell WG: The human myosin light chain kinase (MLCK) from hippocampus: cloning, sequencing, expression, and localization to 3qcen-q21. Genomics. 1995 Oct 10;29(3):562-70. doi: 10.1006/geno.1995.9965.
Pubmed: 8575746
Garcia JG, Lazar V, Gilbert-McClain LI, Gallagher PJ, Verin AD: Myosin light chain kinase in endothelium: molecular cloning and regulation. Am J Respir Cell Mol Biol. 1997 May;16(5):489-94. doi: 10.1165/ajrcmb.16.5.9160829.
Pubmed: 9160829
Wawrzynczak EJ, Perham RN: Isolation and nucleotide sequence of a cDNA encoding human calmodulin. Biochem Int. 1984 Aug;9(2):177-85.
Pubmed: 6385987
Rhyner JA, Ottiger M, Wicki R, Greenwood TM, Strehler EE: Structure of the human CALM1 calmodulin gene and identification of two CALM1-related pseudogenes CALM1P1 and CALM1P2. Eur J Biochem. 1994 Oct 1;225(1):71-82. doi: 10.1111/j.1432-1033.1994.00071.x.
Pubmed: 7925473
Heilig R, Eckenberg R, Petit JL, Fonknechten N, Da Silva C, Cattolico L, Levy M, Barbe V, de Berardinis V, Ureta-Vidal A, Pelletier E, Vico V, Anthouard V, Rowen L, Madan A, Qin S, Sun H, Du H, Pepin K, Artiguenave F, Robert C, Cruaud C, Bruls T, Jaillon O, Friedlander L, Samson G, Brottier P, Cure S, Segurens B, Aniere F, Samain S, Crespeau H, Abbasi N, Aiach N, Boscus D, Dickhoff R, Dors M, Dubois I, Friedman C, Gouyvenoux M, James R, Madan A, Mairey-Estrada B, Mangenot S, Martins N, Menard M, Oztas S, Ratcliffe A, Shaffer T, Trask B, Vacherie B, Bellemere C, Belser C, Besnard-Gonnet M, Bartol-Mavel D, Boutard M, Briez-Silla S, Combette S, Dufosse-Laurent V, Ferron C, Lechaplais C, Louesse C, Muselet D, Magdelenat G, Pateau E, Petit E, Sirvain-Trukniewicz P, Trybou A, Vega-Czarny N, Bataille E, Bluet E, Bordelais I, Dubois M, Dumont C, Guerin T, Haffray S, Hammadi R, Muanga J, Pellouin V, Robert D, Wunderle E, Gauguet G, Roy A, Sainte-Marthe L, Verdier J, Verdier-Discala C, Hillier L, Fulton L, McPherson J, Matsuda F, Wilson R, Scarpelli C, Gyapay G, Wincker P, Saurin W, Quetier F, Waterston R, Hood L, Weissenbach J: The DNA sequence and analysis of human chromosome 14. Nature. 2003 Feb 6;421(6923):601-7. doi: 10.1038/nature01348. Epub 2003 Jan 1.
Pubmed: 12508121
Maldonado F, Hanks SK: A cDNA clone encoding human cAMP-dependent protein kinase catalytic subunit C alpha. Nucleic Acids Res. 1988 Aug 25;16(16):8189-90. doi: 10.1093/nar/16.16.8189.
Pubmed: 2843813
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
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
Beebe SJ, Oyen O, Sandberg M, Froysa A, Hansson V, Jahnsen T: Molecular cloning of a tissue-specific protein kinase (C gamma) from human testis--representing a third isoform for the catalytic subunit of cAMP-dependent protein kinase. Mol Endocrinol. 1990 Mar;4(3):465-75. doi: 10.1210/mend-4-3-465.
Pubmed: 2342480
Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I: The full-ORF clone resource of the German cDNA Consortium. BMC Genomics. 2007 Oct 31;8:399. doi: 10.1186/1471-2164-8-399.
Pubmed: 17974005
Groussin L, Jullian E, Perlemoine K, Louvel A, Leheup B, Luton JP, Bertagna X, Bertherat J: Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab. 2002 Sep;87(9):4324-9. doi: 10.1210/jc.2002-020592.
Pubmed: 12213893
Sandberg M, Tasken K, Oyen O, Hansson V, Jahnsen T: Molecular cloning, cDNA structure and deduced amino acid sequence for a type I regulatory subunit of cAMP-dependent protein kinase from human testis. Biochem Biophys Res Commun. 1987 Dec 31;149(3):939-45. doi: 10.1016/0006-291x(87)90499-2.
Pubmed: 3426618
Sandberg M, Skalhegg B, Jahnsen T: The two mRNA forms for the type I alpha regulatory subunit of cAMP-dependent protein kinase from human testis are due to the use of different polyadenylation site signals. Biochem Biophys Res Commun. 1990 Feb 28;167(1):323-30. doi: 10.1016/0006-291x(90)91768-n.
Pubmed: 2310396
Manchev VT, Hilpert M, Berrou E, Elaib Z, Aouba A, Boukour S, Souquere S, Pierron G, Rameau P, Andrews R, Lanza F, Bobe R, Vainchenker W, Rosa JP, Bryckaert M, Debili N, Favier R, Raslova H: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene. Blood. 2014 Oct 16;124(16):2554-63. doi: 10.1182/blood-2014-01-551820. Epub 2014 Jul 24.
Pubmed: 25061177
Reinton N, Haugen TB, Orstavik S, Skalhegg BS, Hansson V, Jahnsen T, Tasken K: The gene encoding the C gamma catalytic subunit of cAMP-dependent protein kinase is a transcribed retroposon. Genomics. 1998 Apr 15;49(2):290-7. doi: 10.1006/geno.1998.5240.
Pubmed: 9598317
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