Nicotine Activity on Dopaminergic Neurons (Homo sapiens)

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

History

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47517view11:40, 24 March 2012Madhu RohiniModified title
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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
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38480view18:20, 17 September 2010AlexanderPicoModified description
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External references

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