Nicotine effect on dopaminergic neurons (WP1602)

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: [https://www.pharmgkb.org/pathway/PA162355621 Nicotine Pathway in Dopaminergic Neurons (PharmGKB)], [http://en.wikipedia.org/wiki/Nicotine Nicotine (Wikipedia)]. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP1602 CPTAC Assay Portal]
last edited

Authors

Khanspers, Boghog, AlexanderPico, MaintBot, Madhu Rohini, Cizar, DeSl, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Cell Type Ontology: dopaminergic neuron

Pathway Ontology: nicotine drug pathway

Participants

Label Type Compact Identifier
CHRNA4 GeneProduct ncbigene:1137
GNAI1 GeneProduct ncbigene:2770
TH GeneProduct ncbigene:7054
Na+ Metabolite hmdb:HMDB0000588
PRKACA GeneProduct ncbigene:5566
Dopamine Metabolite hmdb:HMDB0000073
DRD2 GeneProduct ncbigene:1813
SNARE Complex GeneProduct None
CDK5 GeneProduct ncbigene:1020
CHRNA4 GeneProduct ncbigene:1137
DRD4 GeneProduct ncbigene:1815
CHRNA4 GeneProduct ncbigene:1137
Tyrosine Metabolite hmdb:HMDB0000158
PPP1R1B GeneProduct ncbigene:84152
DRD3 GeneProduct ncbigene:1814
Dopamine Metabolite hmdb:HMDB0000073
ADCY2 GeneProduct ncbigene:108
DRD2 GeneProduct ncbigene:1813
ATP Metabolite hmdb:HMDB0000538
PPP1R1B GeneProduct ncbigene:84152
DDC GeneProduct ncbigene:1644
Dopamine Metabolite hmdb:HMDB0000073
CHRNA5 GeneProduct ncbigene:1138
Dopamine Metabolite hmdb:HMDB0000073
CHRNB2 GeneProduct ncbigene:1141
Ca++ Metabolite hmdb:HMDB0000464
GNAI1 GeneProduct ncbigene:2770
GNB1 GeneProduct ncbigene:2782
K+ Metabolite hmdb:HMDB0000586
K+ Metabolite hmdb:HMDB0000586
K+ Metabolite hmdb:HMDB0000586
DOPA Metabolite hmdb:HMDB0000181
KCNK9 GeneProduct ncbigene:51305
CHRNB2 GeneProduct ncbigene:1141
SLC18A2 GeneProduct ncbigene:6571
PPP1R1B GeneProduct ncbigene:84152
Nicotine Metabolite hmdb:HMDB0001934
DRD4 GeneProduct ncbigene:1815
CHRNA6 GeneProduct ncbigene:8973
PPP1CA GeneProduct ncbigene:5499
Ca++ Metabolite hmdb:HMDB0000464
GNG2 GeneProduct ncbigene:54331
KCNK3 GeneProduct ncbigene:3777
CHRNA3 GeneProduct ncbigene:1136
cAMP Metabolite hmdb:HMDB0000058
GNG2 GeneProduct ncbigene:54331
CHRNB2 GeneProduct ncbigene:1141
Na+ Metabolite hmdb:HMDB0000588
DRD3 GeneProduct ncbigene:1814
K+ Metabolite hmdb:HMDB0000586
GNB1 GeneProduct ncbigene:2782

References

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