Pathway Selective Serotonin Reuptake Inhibitor Pathway, Pharmacodynamics

Genes involved in serotonin synthesis, release, reuptake, and in mediation of the antidepressant effect of selective serotonin reuptake inhibitors (SSRI) in human brain.
Selective Serotonin Reuptake Inhibitor Pathway, Pharmacodynamics
tph ddc maoa slc18a2 htr1 slc6a4 htr3a htr2 htr1 htr4 htr6 htr7 gnaq plcb gnai gnas adcy ssri
clickable pathway icons
Reproductions of this diagram can be used with permission from PharmGKB. Request permission


Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that influences multiple processes, including autonomic function, motor activity, hormone secretion, cognition, and complex processes associated with affection, emotion, and reward [#1].

In the terminal axon of the serotonergic neuron, free tryptophan (TRP) is converted to 5-HT [#2]. 5-HT synthesis is a two-step process catalyzed by tryptophan hydroxylase (TPH) and aromatic decarboxylase (DDC). TPH is the rate-limiting enzyme and exists in two isoforms TPH1 and TP# The TPH2 isoform is the predominant form in neuronal tissue [#3], [#4]. The 5-HT uptake into presynaptic storage vesicles is mediated by the vesicular monoamine transporter (SLC18A2). The transporter accumulates serotonin into synaptic vesicles using a proton gradient across the vesicular membrane [#5]. 5-HT that is not stored in vesicles is degraded by monoamine oxidase A (MAOA) to 5-hydroxyindoleacetic acid (5-HIAA).

An action potential stimulates a calcium-dependent exocytotic release of serotonin from presynaptic vesicles into the synaptic cleft, where it interacts with both post- and presynaptic receptors. At the presynaptic side, 5-HT activates 5-hydroxytryptamine (serotonin) receptor 1A (HTR1A), B (HTR1B), and D (HTR1D), which results in an attenuation of the 5-HT exocytosis [#2]. This feedback loop regulates the 5-HT concentration in the synaptic cleft and therefore, the extent of stimulation of various HTR receptor subclasses at the postsynaptic membrane [#6]. Prolonged administration of selective serotonin reuptake inhibitors (SSRI) desensitizes these feedback loops. Thus, their regulatory effects on the serotonergic neurotransmission are weakened [#7]. Postsynaptic HTR1 receptors (HTR1A, HTR1B, HTR1D, HTR1E, HTR1F) work together with HTR2 receptor subtypes (HTR2A, HTR2C) in mediating effector signals via activation of second messenger cascades [#2]. Postsynaptic, the main signaling pathway for HTR1 receptor subtypes is via coupling of Gi/o protein alpha subunit (GNAI). This interaction decreases cyclic AMP formation by inhibiting adenylate cyclases (ADCY) [#8]. After interaction with 5-HT, the main signaling linkage for the HTR2 receptor subpopulation is to activate phospholipase C (PLCB) through coupling of Gq/11 protein alpha (GNAQ) [#8]. PLCB catalyzes the formation of myoinositol- 1, 4, 5-trisphosphate (IP3) and diacylglycerol (DAG) [#9].The postsynaptic, ionotropic HTR3 receptor is a cation-specific ligand-gated ion channel, which does not activate a second messenger system [#10]. The binding of 5-HT to this receptor depolarizes the postsynaptic membrane by sodium influx and potassium efflux, which is assumed to influence the activation of HTR2 receptors. HTR4, HTR6, and HTR7 primarily couple Gs protein alpha (GNAS), which results in an activation of adenylate cyclase, and consequently in an increase of cyclic AMP levels [#9]. Further operational diversity is supported by the existence of a great number of splice and editing variants for several HTRs, their possible modulation by accessory proteins and chaperones, as well as their potential to form homo or heteromers both at the GPCR and at the ligand-gated channel level [#11].

The amplification of all those second messenger signals in further downstream reactions leads to the mediation of neurotransmitter release from central serotonergic, noradrenergic, and dopaminergic neurons in the brain by regulating potassium channels, several protein kinases, and other calcium dependent signals.

Chronic administration of antidepressant treatments have been reported to commonly increase the expression of brain-derived neurotrophic factor (BDNF), an activity-dependent secreted protein that is critical to organization of neuronal networks and synaptic plasticity [#12], [#13].

The solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4) is responsible for terminating the action of 5-HT in the synaptic cleft. Released serotonin is transported back into the presynaptic terminals via this integral membrane protein. SLC6A4 is a member of the Na+/Cl--dependent transporter family [#14].

Four major classes of antidepressant drugs exist: monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRI), tricyclic compounds, and atypical antidepressant drugs [#7]. To date, no comprehensive hypothesis concerning the antidepressant action for those therapies has been established [#15]. Nonetheless, those drugs have one or more primary molecular targets in order to act. The molecular target for SSRI is SLC6A4, resulting in an inhibition of 5-HT reuptake in the presynapse from the synaptic cleft. The five SSRI fluoxetine, fluoxamine, paroxetine, sertraline, and citalopram vary in their pharmacological profile resulting in differential efficacy or side-effect profile for particular patients [#16], [#17], [#18]. SSRI have a high affinity for 5-HT uptake transporters, low affinity for noradrenaline uptake transporters, and very low affinity for neurotransmitter receptors.

The observation that current antidepressant therapies need a sustained treatment of 2¿4 weeks to be effective suggests that adaptive changes in both serotonergic and noradrenergic neurotransmission and downstream neural adaptation (e.g. the BDNF receptor signaling pathway) rather than only the elevation in synaptic monoamine levels itself are responsible for the therapeutic effects [#19], [#20].

Several genetic polymorphisms have been associated with therapeutic SSRI response and also with adverse reaction, including genetic variants of the SLC6A4, HTR1A, HTR2A, HTR3B, TPH, BDNF, and G-protein beta3 subunit [#10], [#13], [#21], [#22].

  1. {anchor:1}Zhou M, Engel K, Wang J: Evidence for significant contribution of a newly identified transporter (PMAT) to serotonin uptake in the human brain. Biochem Pharmacol 2007; 73:147-154.
  2. {anchor:2}Struder HK, Weicker H: Physiology and pathophysiology of the serotonergic system and its implications on mental and physical performance. Part I. Int J Sports Med 2001; 22:467-481.
  3. {anchor:3}Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M: Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003; 299:76.
  4. {anchor:4}Sakowski SA, Geddes TJ, Thomas DM, Levi E, Hatfield JS, Kuhn DM: Differential tissue distribution of tryptophan hydroxylase isoforms 1 and 2 as revealed with monospecific antibodies. Brain Res 2006; 1085:11-18.
  5. {anchor:5}Hoffman BJ, Hansson SR, Mezey E, Palkovits M: Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front Neuroendocrinol 1998; 19:187-231.
  6. {anchor:6}Boadle-Biber MC: Regulation of serotonin synthesis. Prog Biophys Mol Biol 1993; 60:1-15.
  7. {anchor:7}Briley M, Moret C: Neurobiological mechanisms involved in antidepressant therapies. Clin Neuropharmacol 1993; 16:387-400.
  8. {anchor:8}Bockaert J, Claeysen S, Becamel C, Dumuis A, Marin P: Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 2006; 326:553-572.
  9. {anchor:9}Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN: Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 2001; 92:179-212.
  10. {anchor:10}Niesler B, Kapeller J, Hammer C, Rappold G: Serotonin type 3 receptor genes: HTR3A, B, C, D, E. Pharmacogenomics 2008; 9:501-504.
  11. {anchor:11}Hannon J, Hoyer D: Molecular biology of 5-HT receptors. Behav Brain Res 2008; 195:198-213.
  12. {anchor:12}Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I: Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 2008; 1211:37-43.
  13. {anchor:13}Drago A, De Ronchi D, Serretti A: Pharmacogenetics of antidepressant response: an update. Hum Genomics 2009; 3:257-274.
  14. {anchor:14}Quick MW: Regulating the conducting states of a mammalian serotonin transporter. Neuron 2003; 40:537-549.
  15. {anchor:15}Donati RJ, Rasenick MM: G protein signaling and the molecular basis of antidepressant action. Life Sci 2003; 73:1-17.
  16. {anchor:16}Hiemke C, Hartter S: Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther 2000; 85:11-28.
  17. {anchor:17}Cipriani A, La Ferla T, Furukawa TA, Signoretti A, Nakagawa A, Churchill R, McGuire H, Barbui C: Sertraline versus other antidepressive agents for depression. Cochrane Database Syst Rev 2009:CD006117.
  18. {anchor:18}Demyttenaere K, Jaspers L: Review: Bupropion and SSRI-induced side effects. J Psychopharmacol 2008; 22:792-804.
  19. {anchor:19}Vidal R, Valdizan EM, Mostany R, Pazos A, Castro E: Long-term treatment with fluoxetine induces desensitization of 5-HT receptor-dependent signalling and functionality in rat brain. J Neurochem 2009.
  20. {anchor:20}Hashimoto K: Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 2009.
  21. {anchor:21}Serretti A, Artioli P: The pharmacogenomics of selective serotonin reuptake inhibitors. Pharmacogenomics J 2004; 4:233-244.
  22. {anchor:22}Thomas KL, Ellingrod VL: Pharmacogenetics of selective serotonin reuptake inhibitors and associated adverse drug reactions. Pharmacotherapy 2009; 29:822-831.
Authors: Katrin Sangkuhl.
Sangkuhl Katrin, Klein Teri E, Altman Russ B . "Selective serotonin reuptake inhibitors pathway" Pharmacogenetics and genomics (2009).
Therapeutic Categories:
  • Neurological agents

Entities in the Pathway

Genes (28)

Drugs/Drug Classes (5)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
ADCY1, ADCY2 ADCY1, ADCY2 GNAI1, GNAI2, GNAI3, GNAS 11916537, 15034221, 16896947
ATP cyclic AMP ADCY1, ADCY2 12726882
Ca2+ Ca2+ IP3 16896947
diacylglycerol diacylglycerol PLCB1, PLCB2, PLCB3, PLCB4 16896947
GNAI1, GNAI2, GNAI3 GNAI1, GNAI2, GNAI3 HTR1A, HTR1B, HTR1D, HTR1E, HTR1F 11590474, 11916537, 12726882
GNAQ GNAQ HTR2A, HTR2C 11590474, 11916537, 12726882
GNAS GNAS HTR4, HTR6, HTR7 11590474, 11916537, 12726882
HTR3A HTR3A serotonin 11590474, 11916537, 12726882
IP3 IP3 PLCB1, PLCB2, PLCB3, PLCB4 16896947
PLCB1, PLCB2, PLCB3, PLCB4 PLCB1, PLCB2, PLCB3, PLCB4 GNAQ 11916537, 15034221, 16896947
serotonin 5-hydroxyindoleacetic acid MAOA 10591056, 14697877
SLC6A4 SLC6A4 citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline 10674711, 14642278, 7969065, 8221701, 9400006
tryptophan serotonin DDC, TPH1, TPH2 10889538, 12511643, 16581041, 8897471
HTR1A, HTR1B, HTR1D, HTR1E, HTR1F HTR1A, HTR1B, HTR1D, HTR1E, HTR1F serotonin 11590474, 11916537, 12726882
HTR1A, HTR1B, HTR1D HTR1A, HTR1B, HTR1D serotonin 11590474, 8480026
HTR2A, HTR2C HTR2A, HTR2C serotonin 11590474, 11916537, 12726882
HTR4 HTR4 serotonin 11590474, 11916537, 12726882
HTR6 HTR6 serotonin 11590474, 11916537, 12726882
HTR7 HTR7 serotonin 11590474, 11916537, 12726882
serotonin serotonin SLC18A2 1438304, 9665836
serotonin serotonin SLC6A4 12769604, 14642278, 8125921

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

Related Publications

Pharmacogenetics of glutamate system genes and SSRI-associated sexual dysfunction. Psychiatry research. 2012. Bishop Jeffrey R, Chae Sharon S, Patel Shitalben, Moline Jessica, Ellingrod Vicki L. PubMed