Nicotine activity on dopaminergic neurons (Mus musculus)

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. 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 Scholia
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 Scholia
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 Scholia

History

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Compare	Revision	Action	Time	User	Comment
	124572	view	15:36, 11 November 2022	Eweitz	Modified title
	106867	view	13:34, 17 September 2019	MaintBot	HMDB identifier normalization
	89988	view	19:04, 6 October 2016	Mkutmon	fixed unconnected lines
	78437	view	10:26, 7 January 2015	MaintBot	added missing graphIds
	69911	view	19:35, 11 July 2013	MaintBot	updating to 2013 schema
	58000	view	21:35, 5 February 2013	Ariutta	Periodical save, work in progress
	45985	view	21:16, 1 December 2011	MaintBot	New pathway

External references

DataNodes

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Name	Type	Database reference	Comment
ADCY2	GeneProduct
ATP	Metabolite	HMDB0000538 (HMDB)
CHRNA5	GeneProduct
CHRNA6	GeneProduct
Ca++	Metabolite	HMDB0000464 (HMDB)
Cdk5	GeneProduct	12568 (Entrez Gene)
Chrna3	GeneProduct	110834 (Entrez Gene)
Chrna4	GeneProduct	11438 (Entrez Gene)
Chrnb2	GeneProduct	11444 (Entrez Gene)
DOPA	Metabolite	HMDB0000181 (HMDB)
DRD2	GeneProduct
DRD4	GeneProduct
Ddc	GeneProduct	13195 (Entrez Gene)
Dopamine	Metabolite	HMDB0000073 (HMDB)
Drd3	GeneProduct	13490 (Entrez Gene)
GNAI1	GeneProduct
GNB1	GeneProduct
GNG2	GeneProduct
K+	Metabolite	HMDB0000586 (HMDB)
KCNK9	GeneProduct
Kcnk3	GeneProduct	16527 (Entrez Gene)
Na+	Metabolite	HMDB0000588 (HMDB)
Nicotine	Metabolite	HMDB0001934 (HMDB)
PPP1CA	GeneProduct
PRKACA	GeneProduct
Ppp1r1b	GeneProduct	19049 (Entrez Gene)
SNARE Complex	GeneProduct
Slc18a2	GeneProduct	214084 (Entrez Gene)
Th	GeneProduct	21823 (Entrez Gene)
Tyrosine	Metabolite	HMDB0000158 (HMDB)
cAMP	Metabolite	HMDB0000058 (HMDB)

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