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] e10 dea d64 parentid=Q9UD71; parentsymbol=PPP1R1B; site=MIrRRRPtPAMLFRL; position=thr34; sitegrpid=448047; ptm=p; direction=u parentid=Q9NPC2; parentsymbol=KCNK9; site=RLMKRRKsV______; position=ser373; sitegrpid=18609100; ptm=p; direction=u parentid=Q9UD71; parentsymbol=PPP1R1B; site=RPNPCAytPPsLKAV; position=thr75; sitegrpid=448048; ptm=p; direction=u e38 b43 nicotine pathway PW:0000721 Pathway Ontology 11908751 PubMed Integrating genotype and phenotype information: an overview of the PharmGKB project. Pharmacogenetics Research Network and Knowledge Base. Pharmacogenomics J 2001 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 dopaminergic neuron CL:0000700 Cell Type 700 PubMed mine wikipathways.org 1999 700 PubMed mine wikipathways.org 1999 700 PubMed [Circadian variations of the activity and induction of tyrosine aminotransferase after x-irradiation]. Physiologie 1975 Stefan M Boerescu J Gheorghe N 7888 PubMed [Conservative therapy of coronary heart disease]. Verh Dtsch Ges Kreislaufforsch 1975 Kaltenbach M 12827358 PubMed The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine. Pflugers Arch 2004 Eiden LE Schäfer MK Weihe E Schütz B 19903816 PubMed A biochemical and functional protein complex involving dopamine synthesis and transport into synaptic vesicles. J Biol Chem 2010 Cartier EA Parra LA Baust TB Quiroz M Salazar G Faundez V Egaña L Torres GE