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Pathway Description
Bromocriptine Mechanism of Action Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2023-08-14
Last Updated: 2023-11-27
Bromocriptine is an ergot alkaloid derivative in the dopamine D2 agonist class of drugs. Prolactin release-inhibiting hormone (PRIH) is the catecholamine neurotransmitter dopamine. Bromocriptine is an FDA-approved medication indicated for the use of disorders causing hyperprolactinemia, which most often is due to the most common of the pituitary adenomas – prolactinoma. Bromocriptine is a dopamine receptor agonist with selective agonist activity on D2 dopamine receptors while simultaneously acting as a partial antagonist for D1 dopamine receptors. Dopamine agonism has variable effects depending on the target tissue. In Parkinson disease, bromocriptine binds directly to striatal dopamine D2 receptors, stimulating locomotion and attenuating the bradykinetic symptoms caused by the degeneration of dopaminergic nigrostriatal neurons. This same D2 agonistic effect on the D2 receptors of anterior pituitary lactotrophic cells blocks prolactin exocytosis and gene expression, reducing the harmful effects of hyperprolactinemia in the case of a pituitary prolactinoma. In acromegaly, bromocriptine’s dopaminergic effect can cause paradoxical blocking of GH release through tuberoinfundibular pathways, decreasing circulating blood concentrations of GH. he dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with Gi proteins. In lactotrophs, stimulation of dopamine D2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca2+ from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders.
References
Bromocriptine Mechanism of Action Pathway References
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
Al-Chalabi M, Bass AN, Alsalman I: Physiology, Prolactin.
Pubmed: 29939606
Liu X, Tang C, Wen G, Zhong C, Yang J, Zhu J, Ma C: The Mechanism and Pathways of Dopamine and Dopamine Agonists in Prolactinomas. Front Endocrinol (Lausanne). 2019 Jan 22;9:768. doi: 10.3389/fendo.2018.00768. eCollection 2018.
Pubmed: 30740089
Ozery M, Wadhwa R: Bromocriptine.
Pubmed: 32310408
Liu X, Tang C, Wen G, Zhong C, Yang J, Zhu J, Ma C: The Mechanism and Pathways of Dopamine and Dopamine Agonists in Prolactinomas. Front Endocrinol (Lausanne). 2019 Jan 22;9:768. doi: 10.3389/fendo.2018.00768. eCollection 2018.
Pubmed: 30740089
Kaneda N, Kobayashi K, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T: Isolation of a novel cDNA clone for human tyrosine hydroxylase: alternative RNA splicing produces four kinds of mRNA from a single gene. Biochem Biophys Res Commun. 1987 Aug 14;146(3):971-5. doi: 10.1016/0006-291x(87)90742-x.
Pubmed: 2887169
Grima B, Lamouroux A, Boni C, Julien JF, Javoy-Agid F, Mallet J: A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics. Nature. 1987 Apr 16-22;326(6114):707-11. doi: 10.1038/326707a0.
Pubmed: 2882428
Kobayashi K, Kaneda N, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T: Isolation of a full-length cDNA clone encoding human tyrosine hydroxylase type 3. Nucleic Acids Res. 1987 Aug 25;15(16):6733. doi: 10.1093/nar/15.16.6733.
Pubmed: 2888085
Ichinose H, Kurosawa Y, Titani K, Fujita K, Nagatsu T: Isolation and characterization of a cDNA clone encoding human aromatic L-amino acid decarboxylase. Biochem Biophys Res Commun. 1989 Nov 15;164(3):1024-30. doi: 10.1016/0006-291x(89)91772-5.
Pubmed: 2590185
Scherer LJ, McPherson JD, Wasmuth JJ, Marsh JL: Human dopa decarboxylase: localization to human chromosome 7p11 and characterization of hepatic cDNAs. Genomics. 1992 Jun;13(2):469-71.
Pubmed: 1612608
Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T: Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis. Biochemistry. 1992 Mar 3;31(8):2229-38. doi: 10.1021/bi00123a004.
Pubmed: 1540578
Surratt CK, Persico AM, Yang XD, Edgar SR, Bird GS, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR: A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs. FEBS Lett. 1993 Mar 8;318(3):325-30. doi: 10.1016/0014-5793(93)80539-7.
Pubmed: 8095030
Erickson JD, Eiden LE: Functional identification and molecular cloning of a human brain vesicle monoamine transporter. J Neurochem. 1993 Dec;61(6):2314-7. doi: 10.1111/j.1471-4159.1993.tb07476.x.
Pubmed: 8245983
Peter D, Finn JP, Klisak I, Liu Y, Kojis T, Heinzmann C, Roghani A, Sparkes RS, Edwards RH: Chromosomal localization of the human vesicular amine transporter genes. Genomics. 1993 Dec;18(3):720-3.
Pubmed: 7905859
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. doi: 10.1016/0896-6273(92)90109-q.
Pubmed: 1309651
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
Brust PF, Simerson S, McCue AF, Deal CR, Schoonmaker S, Williams ME, Velicelebi G, Johnson EC, Harpold MM, Ellis SB: Human neuronal voltage-dependent calcium channels: studies on subunit structure and role in channel assembly. Neuropharmacology. 1993 Nov;32(11):1089-102. doi: 10.1016/0028-3908(93)90004-m.
Pubmed: 8107964
Klugbauer N, Lacinova L, Marais E, Hobom M, Hofmann F: Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci. 1999 Jan 15;19(2):684-91.
Pubmed: 9880589
Gao B, Sekido Y, Maximov A, Saad M, Forgacs E, Latif F, Wei MH, Lerman M, Lee JH, Perez-Reyes E, Bezprozvanny I, Minna JD: Functional properties of a new voltage-dependent calcium channel alpha(2)delta auxiliary subunit gene (CACNA2D2). J Biol Chem. 2000 Apr 21;275(16):12237-42. doi: 10.1074/jbc.275.16.12237.
Pubmed: 10766861
Hobom M, Dai S, Marais E, Lacinova L, Hofmann F, Klugbauer N: Neuronal distribution and functional characterization of the calcium channel alpha2delta-2 subunit. Eur J Neurosci. 2000 Apr;12(4):1217-26. doi: 10.1046/j.1460-9568.2000.01009.x.
Pubmed: 10762351
Williams ME, Brust PF, Feldman DH, Patthi S, Simerson S, Maroufi A, McCue AF, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel. Science. 1992 Jul 17;257(5068):389-95. doi: 10.1126/science.1321501.
Pubmed: 1321501
Humphray SJ, Oliver K, Hunt AR, Plumb RW, Loveland JE, Howe KL, Andrews TD, Searle S, Hunt SE, Scott CE, Jones MC, Ainscough R, Almeida JP, Ambrose KD, Ashwell RI, Babbage AK, Babbage S, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beasley H, Beasley O, Bird CP, Bray-Allen S, Brown AJ, Brown JY, Burford D, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Chen Y, Clarke G, Clark SY, Clee CM, Clegg S, Collier RE, Corby N, Crosier M, Cummings AT, Davies J, Dhami P, Dunn M, Dutta I, Dyer LW, Earthrowl ME, Faulkner L, Fleming CJ, Frankish A, Frankland JA, French L, Fricker DG, Garner P, Garnett J, Ghori J, Gilbert JG, Glison C, Grafham DV, Gribble S, Griffiths C, Griffiths-Jones S, Grocock R, Guy J, Hall RE, Hammond S, Harley JL, Harrison ES, Hart EA, Heath PD, Henderson CD, Hopkins BL, Howard PJ, Howden PJ, Huckle E, Johnson C, Johnson D, Joy AA, Kay M, Keenan S, Kershaw JK, Kimberley AM, King A, Knights A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd C, Lloyd DM, Lovell J, Martin S, Mashreghi-Mohammadi M, Matthews L, McLaren S, McLay KE, McMurray A, Milne S, Nickerson T, Nisbett J, Nordsiek G, Pearce AV, Peck AI, Porter KM, Pandian R, Pelan S, Phillimore B, Povey S, Ramsey Y, Rand V, Scharfe M, Sehra HK, Shownkeen R, Sims SK, Skuce CD, Smith M, Steward CA, Swarbreck D, Sycamore N, Tester J, Thorpe A, Tracey A, Tromans A, Thomas DW, Wall M, Wallis JM, West AP, Whitehead SL, Willey DL, Williams SA, Wilming L, Wray PW, Young L, Ashurst JL, Coulson A, Blocker H, Durbin R, Sulston JE, Hubbard T, Jackson MJ, Bentley DR, Beck S, Rogers J, Dunham I: DNA sequence and analysis of human chromosome 9. Nature. 2004 May 27;429(6990):369-74. doi: 10.1038/nature02465.
Pubmed: 15164053
Kim DS, Jung HH, Park SH, Chin H: Isolation and characterization of the 5'-upstream region of the human N-type calcium channel alpha1B subunit gene. Chromosomal localization and promoter analysis. J Biol Chem. 1997 Feb 21;272(8):5098-104. doi: 10.1074/jbc.272.8.5098.
Pubmed: 9030575
Vandenbergh DJ, Persico AM, Uhl GR: A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs. Brain Res Mol Brain Res. 1992 Sep;15(1-2):161-6. doi: 10.1016/0169-328x(92)90165-8.
Pubmed: 1359373
Giros B, el Mestikawy S, Godinot N, Zheng K, Han H, Yang-Feng T, Caron MG: Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. Mol Pharmacol. 1992 Sep;42(3):383-90.
Pubmed: 1406597
Pristupa ZB, Wilson JM, Hoffman BJ, Kish SJ, Niznik HB: Pharmacological heterogeneity of the cloned and native human dopamine transporter: disassociation of [3H]WIN 35,428 and [3H]GBR 12,935 binding. Mol Pharmacol. 1994 Jan;45(1):125-35.
Pubmed: 8302271
Kazatskaya A, Kuhns S, Lambacher NJ, Kennedy JE, Brear AG, McManus GJ, Sengupta P, Blacque OE: Primary Cilium Formation and Ciliary Protein Trafficking Is Regulated by the Atypical MAP Kinase MAPK15 in Caenorhabditis elegans and Human Cells. Genetics. 2017 Dec;207(4):1423-1440. doi: 10.1534/genetics.117.300383. Epub 2017 Oct 11.
Pubmed: 29021280
Abe MK, Saelzler MP, Espinosa R 3rd, Kahle KT, Hershenson MB, Le Beau MM, Rosner MR: ERK8, a new member of the mitogen-activated protein kinase family. J Biol Chem. 2002 May 10;277(19):16733-43. doi: 10.1074/jbc.M112483200. Epub 2002 Mar 1.
Pubmed: 11875070
Iavarone C, Acunzo M, Carlomagno F, Catania A, Melillo RM, Carlomagno SM, Santoro M, Chiariello M: Activation of the Erk8 mitogen-activated protein (MAP) kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene. J Biol Chem. 2006 Apr 14;281(15):10567-76. doi: 10.1074/jbc.M513397200. Epub 2006 Feb 16.
Pubmed: 16484222
Owaki H, Makar R, Boulton TG, Cobb MH, Geppert TD: Extracellular signal-regulated kinases in T cells: characterization of human ERK1 and ERK2 cDNAs. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1416-22. doi: 10.1016/0006-291x(92)91891-s.
Pubmed: 1540184
Gonzalez FA, Raden DL, Rigby MR, Davis RJ: Heterogeneous expression of four MAP kinase isoforms in human tissues. FEBS Lett. 1992 Jun 15;304(2-3):170-8. doi: 10.1016/0014-5793(92)80612-k.
Pubmed: 1319925
Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP, et al.: The DNA sequence of human chromosome 22. Nature. 1999 Dec 2;402(6761):489-95. doi: 10.1038/990031.
Pubmed: 10591208
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