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Serotonin 1A Receptor Agonism leading to Anti-depressant Activity via K Channel Opening
Point of Contact
- Timothy Allen
- Cataia Ives
|Handbook Version||OECD status||OECD project|
This AOP was last modified on April 29, 2023 13:02
|Serotonin 1A Receptor Agonism||June 23, 2017 07:16|
|Release of G Proteins||June 08, 2017 12:04|
|Anti-depressant Activity||June 23, 2017 07:18|
|Opening of G protein gated inward rectifying K channels||June 08, 2017 12:04|
|hyperpolarisation, neuron||September 16, 2017 10:16|
|Serotonin 1A Receptor Agonism leads to Release of G Proteins||June 23, 2017 07:18|
|Release of G Proteins leads to Opening of GIRK channels||June 08, 2017 12:11|
|Opening of GIRK channels leads to hyperpolarisation, neuron||June 08, 2017 12:12|
|hyperpolarisation, neuron leads to Anti-depressant Activity||June 23, 2017 07:19|
Serotonin receptors are well-understood GPCRs which trigger cellular signalling via G-proteins. The released G Proteins move to effectors in the cell to initiate their function. For the Gβγ, one of these is the K+ ion channel. The opening of the voltage-sensitive K+ channel allows K+ ions to flow out of the neuron, leading to a decrease in the concentration of K+ in the presynaptic neuron. An increase in the negative charge within the neuron is known as hyperpolarization. Hyperpolarization of a cell membrane inhibits action potentials by increasing the stimulus required to move the membrane potential to the action potential threshold. Serotonin 1A receptors are found in the brain explaining their link to emotional responses.
This putative AOP has been constructed using literature knowledge to provide qualitative information to link in silico predictions to adverse outcomes.
AOP Development Strategy
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||1431||Serotonin 1A Receptor Agonism||Serotonin 1A Receptor Agonism|
|KE||1426||Release of G Proteins||Release of G Proteins|
|KE||1427||Opening of G protein gated inward rectifying K channels||Opening of GIRK channels|
|KE||763||hyperpolarisation, neuron||hyperpolarisation, neuron|
|AO||1432||Anti-depressant Activity||Anti-depressant Activity|
Relationships Between Two Key Events (Including MIEs and AOs)
|Serotonin 1A Receptor Agonism leads to Release of G Proteins||adjacent||High|
|Release of G Proteins leads to Opening of GIRK channels||adjacent||High|
|Opening of GIRK channels leads to hyperpolarisation, neuron||adjacent||High|
|hyperpolarisation, neuron leads to Anti-depressant Activity||non-adjacent||High|
Life Stage Applicability
Overall Assessment of the AOP
Below direct quotes from literature sources provide evidence for each KE and KER.
Serotonin 1A receptor agonism leading to release of G proteins
“there are five known subtypes (of 5HT receptors), all of which are highly conserved and signal through pertussis toxin (PTX)-sensitive Gi/Go proteins” PR Albert 2001
“The 5-HT1 receptors couple to Gi/Go proteins to mediate a range of actions that include classic inhibitory and cell-specific pathways” PR Albert 2001
“The heptahelical, serotonin 1A receptor couples mainly to pertussis toxin (PTX)-sensitive G proteins, such as Gi and Go” T Adayev 2003
“5-HT 1A receptors are coupled to the Gi family of G proteins, which include pertussis toxin-sensitive Gi 1, Gi 2, Gi3 and Go, and pertussis toxin-insensitive Gz proteins” JG Hensler 2003
“The 5-HT 1A receptors activate G i /G o proteins” Z Chilmonczyk 2015
Release of G proteins leading to opening of G protein coupled inward rectifying K channel
“activation of 5HT 1A receptors leads to…activation of hyperpolarizing K channels” SO Ogren 2007
“A ubiquitous pathway is…Gβγ-induced opening of K+ channels…mainly in neuroendocrine cells” PR Albert 2001
“5-HT 1A receptors are coupled via pertussis toxin-sensitive G proteins to the inhibition of adenylyl cyclase, or to the opening of potassium channels” JG Hensler 2003
“In neurons, activation of the 5-HT 1A receptor activates G protein-coupled inwardly-rectifying potassium channels (GIRKs) in the hippocampus and in the DRN, an action that profoundly hyperpolarizes neurons and decreases firing” Z Chilmonczyk 2015
Opening of G protein coupled inward rectifying K channel leading to hyperpolarization of presynapse
“Stimulation of the 5-HT1A subtype has been shown to induce neuronal hyperpolarization, most likely mediated by activation of G-protein coupled K+ channels, and consequent inhibition of neuronal activity” E Lacivita 2008
“In the dorsal raphe 5-HT 1A receptor activation opens potassium channels and inhibits cell firing” JG Hensler 2003
“The activation of 5-HT 1A receptors increases potassium conductance, thus hyperpolarizing the neuronal membrane and reducing the firing rate of serotonergic and pyramidal neurons in the cortex and hippocampus” P Celada 2004
Hyperpolarization of presynapse leading to anti-depressant activity
“These agents (5-HT 1A Agonists) comprise a class of psychoactive agents with both anxiolytic and antidepressant effects” JG Hensler 2003
“It should also be noted that the 5-HT 1A receptor cooperates with other signal transduction systems (like the 5-HT 1B or 5-HT 2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity” Z Chilmonczyk 2015
“The ability of 5-HT 1A receptors to activate GIRK-induced hyperpolarizing currents allows them to have a strong effect on neuronal firing and excitability, a physiological process that may be linked to 5-HT 1A receptor-regulated behaviors” Z Chilmonczyk 2015
“5-HT 1A receptors are deeply involved in the mechanism of action of antidepressant drugs” P Celada 2004
“5-HT1A receptors are deeply involved in the mechanism of action of antidepressant drugs. They occur in mammalian brain in 2 different populations: on 5-HT neurons of the midbrain raphe nuclei (autoreceptors) and on neurons postsynaptic to 5-HT nerve terminals, mainly in cortico-limbic areas. In both regions, 5-HT1A receptors have a somatodendritic location. The activation of 5-HT1A receptors increases potassium conductance, thus hyperpolarizing the neuronal membrane and reducing the firing rate of serotonergic and pyramidal neurons in the cortex and hippocampus” P Celada 2004
Domain of Applicability
Essentiality of the Key Events
Known Modulating Factors
Considerations for Potential Applications of the AOP (optional)
Adayev T., Ray I., Sondhi R., Sobocki T., Banerjee P. (2003) Biochim. Biophys. Acta-Molecular Cell Res. 1640, 8.
Albert P.R., Tiberi M. (2001) Trends Endocrinol. Metab. 12, 453.
Celada P., Puig M.V., Amargós-Bosch M., Adell A., Artigas F. (2004) J. Psychiatry Neurosci. 29, 252.
Chilmonczyk Z., Bojarski A.J., Pilc, A., and Sylte, I. (2015) Int. J. Mol. Sci. 16, 18474.
Hensler J.G. (2003) Life Sci. 72, 1665.
Lacivita E., Leopoldo M., Berardi F., Perrone R. (2008) Curr. Top. Med. Chem. 8, 1024.
Ögren S.O., Razani H., Elvander-Tottie E., Kehr J. (2007) Physiol. Behav. 92, 172.