Nicotine Activity on Dopaminergic Neurons (Bos taurus)

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2, 51Synaptic VesiclePDopaminergic neuronDepolarizationThr75PThr34PDRD3DRD2PPP1R1BGNB1PPP1R1BDopamineKCNK9CHRNA5K+GNAI1CHRNA4ADCY2DopamineSLC18A2DDCNa+KCNK3CHRNA4GNAI1GNB1DRD4PPP1R1BDopamineCHRNB2Ca++CHRNA3K+THK+Ca++K+CHRNB2PRKACANicotineDRD4CHRNA6CDK5DopamineCHRNA4Na+cAMPGNG2CHRNB2SNARE ComplexGNG2DRD2TyrosineATPDOPAPPP1CADRD343


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(78486) with a 91.0% conversion rate.

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Bibliography

  1. 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
  2. martin, grady; ''mine''; wikipathways.org, 1999 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
  4. Kaltenbach M; ''[Conservative therapy of coronary heart disease].''; Verh Dtsch Ges Kreislaufforsch, 1975 PubMed Europe PMC
  5. 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

History

CompareRevisionActionTimeUserComment
106010view11:53, 16 August 2019MaintBotHMDB identifier normalization
80757view15:24, 30 June 2015MkutmonNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADCY2GeneProductENSBTAG00000019210 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:108
ATPMetaboliteHMDB0000538 (HMDB)
CDK5GeneProductENSBTAG00000007766 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1020
CHRNA3GeneProductENSBTAG00000003130 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1136
CHRNA4GeneProductENSBTAG00000017198 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1137
CHRNA5GeneProductENSBTAG00000013657 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1138
CHRNA6GeneProductENSBTAG00000014056 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8973
CHRNB2GeneProductENSBTAG00000007517 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1141
Ca++MetaboliteHMDB0000464 (HMDB)
DDCGeneProductENSBTAG00000020869 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1644
DOPAMetaboliteHMDB0000181 (HMDB)
DRD2GeneProductENSBTAG00000010860 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1813
DRD3GeneProductENSBTAG00000002132 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1814
DRD4GeneProduct
DopamineMetaboliteHMDB0000073 (HMDB)
GNAI1GeneProductENSBTAG00000002714 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2770
GNB1GeneProductENSBTAG00000000215 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2782
GNG2GeneProductENSBTAG00000003043 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54331
K+MetaboliteHMDB0000586 (HMDB)
KCNK3GeneProductENSBTAG00000018193 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3777
KCNK9GeneProductENSBTAG00000047488 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51305
Na+MetaboliteHMDB0000588 (HMDB)
NicotineMetaboliteHMDB0001934 (HMDB)
PPP1CAGeneProductENSBTAG00000040418 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5499
PPP1R1BGeneProductENSBTAG00000006035 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:84152
PRKACAGeneProductENSBTAG00000006642 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5566
SLC18A2GeneProductENSBTAG00000004739 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6571
SNARE ComplexGeneProduct
THGeneProductENSBTAG00000026768 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7054
TyrosineMetaboliteHMDB0000158 (HMDB)
cAMPMetaboliteHMDB0000058 (HMDB)

Annotated Interactions

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