Nicotine activity on dopaminergic neurons (WP3179)

Bos taurus

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: [http://www.pharmgkb.org/do/serve?objId=PA162355621&objCls=Pathway PharmGKB:Nicotine in Dopaminergic Neurons], [http://en.wikipedia.org/wiki/Nicotine Wikipedia:Nicotine]

Authors

Martina Summer-Kutmon and Eric Weitz

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

nicotine drug pathway

Cell Type Ontology

dopaminergic neuron

Participants

Label Type Compact URI Comment
Na+ Metabolite hmdb:HMDB0000588
Dopamine Metabolite hmdb:HMDB0000073
Tyrosine Metabolite hmdb:HMDB0000158
ATP Metabolite hmdb:HMDB0000538
Ca++ Metabolite hmdb:HMDB0000464
K+ Metabolite hmdb:HMDB0000586
DOPA Metabolite hmdb:HMDB0000181
Nicotine Metabolite hmdb:HMDB0001934
cAMP Metabolite hmdb:HMDB0000058
CHRNA4 GeneProduct ensembl:ENSBTAG00000017198 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1137
GNAI1 GeneProduct ensembl:ENSBTAG00000002714 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2770
TH GeneProduct ensembl:ENSBTAG00000026768 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7054
PRKACA GeneProduct ensembl:ENSBTAG00000006642 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5566
DRD2 GeneProduct ensembl:ENSBTAG00000010860 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1813
CDK5 GeneProduct ensembl:ENSBTAG00000007766 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1020
PPP1R1B GeneProduct ensembl:ENSBTAG00000006035 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:84152
DRD3 GeneProduct ensembl:ENSBTAG00000002132 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1814
ADCY2 GeneProduct ensembl:ENSBTAG00000019210 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:108
DDC GeneProduct ensembl:ENSBTAG00000020869 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1644
CHRNA5 GeneProduct ensembl:ENSBTAG00000013657 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1138
CHRNB2 GeneProduct ensembl:ENSBTAG00000007517 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1141
GNB1 GeneProduct ensembl:ENSBTAG00000000215 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2782
KCNK9 GeneProduct ensembl:ENSBTAG00000047488 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51305
SLC18A2 GeneProduct ensembl:ENSBTAG00000004739 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6571
CHRNA6 GeneProduct ensembl:ENSBTAG00000014056 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8973
PPP1CA GeneProduct ensembl:ENSBTAG00000040418 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5499
GNG2 GeneProduct ensembl:ENSBTAG00000003043 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54331
KCNK3 GeneProduct ensembl:ENSBTAG00000018193 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3777
CHRNA3 GeneProduct ensembl:ENSBTAG00000003130 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1136

References

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