Nicotine effect on dopaminergic neurons (Homo sapiens)

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32PThr75PThr34PDepolarizationSynaptic VesicleDopaminergic neuronGNB1NicotineDopamineGNG2CHRNA5CHRNB2K+DOPAPPP1CAK+SLC18A2DRD3KCNK3DRD2TyrosineK+DopaminecAMPPPP1R1BDRD4GNAI1CHRNA4Na+DRD3DopamineCa++DopamineGNG2CHRNA3PPP1R1BCHRNB2KCNK9SNARE ComplexGNAI1CHRNB2DRD4K+Na+CDK5DDCCHRNA4DRD2CHRNA4Ca++PRKACAGNB1ATPTHADCY2PPP1R1BCHRNA61


Description

Nicotine is an alkaloid found in tobacco plants. It is a substance that acts as a stimulant in humans and is one of the main factors responsible for tobacco dependence. When nicotine enters the body, it is distributed quickly through the bloodstream, and it can cross the blood-brain barrier to enter the central nervous system (CNS). It binds to two main types of nicotinic acetylcholine receptors: the ganglion type and the CNS type.

In dopaminergic neurons in the CNS, nicotine binds to the CNS-type nicotinic acetylcholine receptors. The main type of CNS receptor is composed of alpha 4 beta 2 (CHRNA4, CHRNB2) subunits. It has been shown that alpha 6, alpha 5, and beta 3 can also be in the receptor complex to modulate binding sensitivity. By binding to the receptor, nicotine causes cell depolarization and release of dopamine from the cell through the SNARE complex. Dopamine then binds to dopamine receptors (DRD2, DRD3, DRD4) on dopaminergic terminals and activates Gi alpha (GNAI1), initiating a feedback loop to inhibit dopamine release. One of the key players mediating dopamine signaling is PPP1R1B (also called DARPP-32, dopamine and cyclic AMP-regulated phospho-protein). PPP1R1B is a bifunctional signal transduction molecule which, by distinct mechanisms, inhibits either a serine/threonine kinase (PPKACA or PKA) or a serine/threonine phosphatase (PPP1CA or protein phosphatase 1). When PPP1R1B is phosphorylated by PPKACA at threonine 34, it is an inhibitor of protein phosphatase 1 (PPP1CA), which inhibits dopamine secretion through the SNARE complex. When PPP1R1B is phosphorylated by CDK5 at threonine 75, it is converted to an inhibitor of PPKACA. Binding of dopamine to D2-like dopamine receptors leads to inhibition of adenylate cyclase (ADCY2) via G-protein GNAI1, and decreases PKA-stimulated phosphorylation of DARPP-32 at Thr34. This, in turn, relieves the inhibition of protein phosphatase 1 (PPP1CA), and inhibits further dopamine release.

Sources: PharmGKB:Nicotine in Dopaminergic Neurons, Wikipedia:Nicotine

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Bibliography

  1. Kaltenbach M; ''[Conservative therapy of coronary heart disease].''; Verh Dtsch Ges Kreislaufforsch, 1975 PubMed Europe PMC Scholia
  2. Cartier EA, Parra LA, Baust TB, Quiroz M, Salazar G, Faundez V, Egaña L, Torres GE; ''A biochemical and functional protein complex involving dopamine synthesis and transport into synaptic vesicles.''; J Biol Chem, 2010 PubMed Europe PMC Scholia
  3. Klein TE, Chang JT, Cho MK, Easton KL, Fergerson R, Hewett M, Lin Z, Liu Y, Liu S, Oliver DE, Rubin DL, Shafa F, Stuart JM, Altman RB; ''Integrating genotype and phenotype information: an overview of the PharmGKB project. Pharmacogenetics Research Network and Knowledge Base.''; Pharmacogenomics J, 2001 PubMed Europe PMC Scholia
  4. Eiden LE, Schäfer MK, Weihe E, Schütz B; ''The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine.''; Pflugers Arch, 2004 PubMed Europe PMC Scholia
  5. Stefan M, Boerescu J, Gheorghe N; ''mine''; wikipathways.org, 1999 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
126381view17:58, 25 April 2023EgonwLicense is CCZero
117165view09:50, 18 May 2021EweitzModified title
112075view14:18, 18 September 2020DeSlConnected unconnected line; converted curved arros to straight, updated arrows for translocations of ions/compounds.
111906view22:20, 9 September 2020Khanspersminor updates
111905view22:00, 9 September 2020Khanspersoverhaul: layout, phosphorylation sites, metabolite shapes
107566view20:12, 21 October 2019Khanspersupdated lit ref
107563view19:05, 21 October 2019KhanspersModified description
107562view19:03, 21 October 2019KhanspersReverted to version '21:22, 12 September 2019' by Khanspers
107561view19:03, 21 October 2019KhanspersModified description
106663view21:22, 12 September 2019KhanspersModified description
106180view12:07, 16 August 2019MaintBotHMDB identifier normalization
105664view05:18, 10 August 2019KhanspersModified description
78486view10:28, 7 January 2015MaintBotadded missing graphIds
69773view12:15, 11 July 2013Cizarconnected lines
47517view11:40, 24 March 2012Madhu RohiniModified title
47514view11:23, 24 March 2012Madhu RohiniPeriodical save, work in progress
47513view11:08, 24 March 2012Madhu RohiniModified title
47512view11:07, 24 March 2012Madhu RohiniModified title
47511view10:28, 24 March 2012Madhu RohiniPeriodical save, work in progress
45361view20:49, 7 October 2011KhanspersOntology Term : 'nicotine pathway' added !
45360view20:49, 7 October 2011KhanspersOntology Term : 'dopaminergic neuron' added !
42610view21:27, 10 April 2011AlexanderPicoadded biochemical and functional complex for DA synth and accumulation in vesicles, plus ref
42606view21:15, 10 April 2011AlexanderPicoadded ref for SLC18A2 function
42605view21:14, 10 April 2011AlexanderPicofixed localization of dopamine biosyn and vesicle accumulation
41032view23:15, 1 March 2011MaintBotRemoved redundant pathway information and comments
38611view00:02, 22 September 2010KhanspersModified categories
38610view00:02, 22 September 2010KhanspersChanged title
38481view18:22, 17 September 2010AlexanderPicoattribution listed in Sources
38480view18:20, 17 September 2010AlexanderPicoModified description
38376view15:25, 5 September 2010Boghogadd copyright link
38375view15:24, 5 September 2010BoghogAdded copyright notice and reproduction permission.
38374view15:20, 5 September 2010BoghogAdded reference
38373view15:09, 5 September 2010BoghogModified description
38358view18:11, 2 September 2010KhanspersChanged layout
38344view21:06, 1 September 2010KhanspersChanged name
38343view21:05, 1 September 2010KhanspersModified description
38335view19:06, 1 September 2010KhanspersModified description
38334view18:56, 1 September 2010KhanspersChanged calcium
38333view18:52, 1 September 2010KhanspersModified categories
38332view18:52, 1 September 2010KhanspersModified description
38331view18:51, 1 September 2010KhanspersModified description
38330view18:49, 1 September 2010KhanspersNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADCY2GeneProduct108 (Entrez Gene)
ATPMetaboliteHMDB00538 (HMDB)
CDK5GeneProduct1020 (Entrez Gene)
CHRNA3GeneProduct1136 (Entrez Gene)
CHRNA4GeneProduct1137 (Entrez Gene)
CHRNA5GeneProduct1138 (Entrez Gene)
CHRNA6GeneProduct8973 (Entrez Gene)
CHRNB2GeneProduct1141 (Entrez Gene)
Ca++MetaboliteHMDB00464 (HMDB)
DDCGeneProduct1644 (Entrez Gene)
DOPAMetaboliteHMDB00181 (HMDB)
DRD2GeneProduct1813 (Entrez Gene)
DRD3GeneProduct1814 (Entrez Gene)
DRD4GeneProduct1815 (Entrez Gene)
DopamineMetaboliteHMDB00073 (HMDB)
GNAI1GeneProduct2770 (Entrez Gene)
GNB1GeneProduct2782 (Entrez Gene)
GNG2GeneProduct54331 (Entrez Gene)
K+MetaboliteHMDB00586 (HMDB)
KCNK3GeneProduct3777 (Entrez Gene)
KCNK9GeneProduct51305 (Entrez Gene)
Na+MetaboliteHMDB00588 (HMDB)
NicotineMetaboliteHMDB01934 (HMDB)
PPP1CAGeneProduct5499 (Entrez Gene)
PPP1R1BGeneProduct84152 (Entrez Gene)
PRKACAGeneProduct5566 (Entrez Gene)
SLC18A2GeneProduct6571 (Entrez Gene)
SNARE ComplexGeneProduct
THGeneProduct7054 (Entrez Gene)
TyrosineMetaboliteHMDB00158 (HMDB)
cAMPMetaboliteHMDB00058 (HMDB)

Annotated Interactions

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