Pathway Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics

Pharmacodynamics
Representation of genes involved in nicotine effects in dopaminergic neurons.
Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics
nicotine chrna4 chrnb2 chrna4 chrnb2 chrna6 chrna3 chrna4 chrnb2 chrna5 kcnk3 kcnk9 ppp1ca ppp1r1b prkaca pppir1b cdk5 pppir1b ddc slc18a2 th adcy2 gnai1 gnb1 gng2 drd2 drd3 drd4 drd2 drd3 drd4 gnai1 gnb1 gng2
clickable pathway icons

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 chromaffin cells in the adrenal medulla, nicotine binds to the ganglion-type nicotinic acetylcholine receptor, which is composed of alpha 3 (CHRNA3) and beta 4 (CHRNB4) subunits. By binding to the receptors, nicotine causes cell depolarization and an influx of calcium through voltage dependent calcium channels. Calcium triggers the release of epinephrine from the chromaffin vesicles into the bloodstream, which leads to increased heart rate and blood pressure and elevation of blood glucose level.

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.

Authors: Huaiyu Mi, Gary E. Swan, Neal Benowitz, Rachel F. Tyndale, Paul D. Thomas, Li Gong.
Citation:
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
If you would like to reproduce this PharmGKB pathway diagram, please acknowledge the copyright to PharmGKB and state that permission has been given by PharmGKB and Stanford University. Also, please send a brief email to feedback@pharmgkb.org to inform us of which pathway diagram you are using and for what purpose.
History:
Therapeutic Categories:
  • Neurological agents

Entities in the Pathway

Genes (48)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
ADCY2 ADCY2 GNAI1 12472880
DOPA dopamine DDC 2590185, 4536745
DRD1/2/3_GNAI1_GNB1_GNG2 (DRD1, DRD2, DRD3, GNAI1, GNB1, GNG2) dopamine, DRD2/3/4 (DRD2, DRD3, DRD4), GNG2_GNB1 (GNB1, GNG2), GNAI1
KCNK3_kcnk9 (KCNK3, KCNK9) KCNK3_kcnk9 (KCNK3, KCNK9) PRKACA 11875121, 12882230
PPP1CA PPP1CA PPP1R1B
PPP1R1B PPP1R1B PRKACA 10433257, 10604473, 17194217, 6087160
PPP1R1B PPP1R1B CDK5 10604473, 17194217
PRKACA PRKACA cAMP, PPP1R1B 10433257, 17194217, 6087160, 9232801
SNARE Complex (SEC22A, SEC22B, SNAP25, STX10, STX11, STX12, STX16, STX17, STX18, STX19, STX1A, STX1B, STX2, STX3, STX4, STX5, STX6, STX7, STX8, VAMP1, VAMP2, VAMP3, VAMP4, VAMP5, VAMP8, YKT6) SNARE Complex (SEC22A, SEC22B, SNAP25, STX10, STX11, STX12, STX16, STX17, STX18, STX19, STX1A, STX1B, STX2, STX3, STX4, STX5, STX6, STX7, STX8, VAMP1, VAMP2, VAMP3, VAMP4, VAMP5, VAMP8, YKT6) PPP1CA 14744247
dopamine DRD1/2/3_GNAI1_GNB1_GNG2 (DRD1, DRD2, DRD3, GNAI1, GNB1, GNG2) 1319557, 1363862, 2129115, 7651368, 8471125
nicotine CHRNA4_CHRNB2 (CHRNA4, CHRNB2) 17597586
nicotine CHRNA4_CHRNB2_CHRNA5 (CHRNA4, CHRNA5, CHRNB2) 12388584, 15155845
nicotine CHRNA4_CHRNB2_CHRNA6_CHRNA3 (CHRNA3, CHRNA4, CHRNA6, CHRNB2) 17341654
ATP cAMP ADCY2 12472880
tyrosine DOPA TH
Ca++ Ca++ CHRNA4_CHRNB2_CHRNA5 (CHRNA4, CHRNA5, CHRNB2), CHRNA4_CHRNB2_CHRNA6_CHRNA3 (CHRNA3, CHRNA4, CHRNA6, CHRNB2) 17341654
dopamine dopamine SLC18A2 1438304
dopamine dopamine SNARE Complex (SEC22A, SEC22B, SNAP25, STX10, STX11, STX12, STX16, STX17, STX18, STX19, STX1A, STX1B, STX2, STX3, STX4, STX5, STX6, STX7, STX8, VAMP1, VAMP2, VAMP3, VAMP4, VAMP5, VAMP8, YKT6)
K+ K+ CHRNA4_CHRNB2 (CHRNA4, CHRNB2) 17597586
K+ K+ KCNK3_kcnk9 (KCNK3, KCNK9)
Na+ Na+ CHRNA4_CHRNB2 (CHRNA4, CHRNB2) 17597586

Download data in TSV format. Other formats are available on the Downloads/LinkOuts tab.