Nicotine Activity on Dopaminergic Neurons (Mus musculus)

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12PPThr34DepolarizationThr75Dopaminergic neuronPSynaptic VesicleCa++DRD2GNB1Ppp1r1bDopamineK+Ca++K+DRD4DopamineThSlc18a2GNAI1Ppp1r1bChrnb2DopamineKcnk3K+Chrna4GNB1Chrna4GNG2Chrna3Ppp1r1bKCNK9Na+Drd3Chrna4NicotineDRD4PRKACAChrnb2CHRNA6TyrosinecAMPCdk5ATPChrnb2ADCY2DOPADRD2GNG2DopamineK+Drd3DdcGNAI1PPP1CASNARE ComplexNa+CHRNA53


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

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP1602(r45361) with a 50% conversion rate.

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Bibliography

  1. 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
  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
  3. 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

History

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CompareRevisionActionTimeUserComment
106867view13:34, 17 September 2019MaintBotHMDB identifier normalization
89988view19:04, 6 October 2016Mkutmonfixed unconnected lines
78437view10:26, 7 January 2015MaintBotadded missing graphIds
69911view19:35, 11 July 2013MaintBotupdating to 2013 schema
58000view21:35, 5 February 2013AriuttaPeriodical save, work in progress
45985view21:16, 1 December 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADCY2GeneProduct
ATPMetaboliteHMDB0000538 (HMDB)
CHRNA5GeneProduct
CHRNA6GeneProduct
Ca++MetaboliteHMDB0000464 (HMDB)
Cdk5GeneProduct12568 (Entrez Gene)
Chrna3GeneProduct110834 (Entrez Gene)
Chrna4GeneProduct11438 (Entrez Gene)
Chrnb2GeneProduct11444 (Entrez Gene)
DOPAMetaboliteHMDB0000181 (HMDB)
DRD2GeneProduct
DRD4GeneProduct
DdcGeneProduct13195 (Entrez Gene)
DopamineMetaboliteHMDB0000073 (HMDB)
Drd3GeneProduct13490 (Entrez Gene)
GNAI1GeneProduct
GNB1GeneProduct
GNG2GeneProduct
K+MetaboliteHMDB0000586 (HMDB)
KCNK9GeneProduct
Kcnk3GeneProduct16527 (Entrez Gene)
Na+MetaboliteHMDB0000588 (HMDB)
NicotineMetaboliteHMDB0001934 (HMDB)
PPP1CAGeneProduct
PRKACAGeneProduct
Ppp1r1bGeneProduct19049 (Entrez Gene)
SNARE ComplexGeneProduct
Slc18a2GeneProduct214084 (Entrez Gene)
ThGeneProduct21823 (Entrez Gene)
TyrosineMetaboliteHMDB0000158 (HMDB)
cAMPMetaboliteHMDB0000058 (HMDB)

Annotated Interactions

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