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Timothy E H Allen, University of Cambridge, email@example.com
Point of Contact
Timothy Allen (email point of contact)
- Timothy Allen
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite||Under Development|
This AOP was last modified on January 28, 2018 23:51
|Serotonin 1A Receptor Agonism||June 23, 2017 07:16|
|Release of G Proteins||June 08, 2017 12:04|
|Inhibition of N-type Ca ion channels||June 23, 2017 06:50|
|Inhibition of neurotransmitter vesicle release||June 23, 2017 06:52|
|Anti-depressant Activity||June 23, 2017 07:18|
|Serotonin 1A Receptor Agonism leads to Release of G Proteins||June 23, 2017 07:18|
|Release of G Proteins leads to Inhibition of Ca Channels||June 23, 2017 06:53|
|Inhibition of Ca Channels leads to Inhibition of neurotransmitter release||June 23, 2017 06:53|
|Inhibition of neurotransmitter release leads to Anti-depressant Activity||June 23, 2017 07:32|
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 Ca2+ ion channel. The inhibition of Ca ion channels prevents the flow of Ca2+ ions into neurons, a key step in the release of neurotransmitters which carry the signal across the synapse to another neuron. A reduction in the ability of neurons to transmit signals between one another causes an emotional suppressant effect in the individual. Serotonin 1A receptors are found in the brain explaining their link to emotional response.
This putative AOP has been constructed using literature knowledge to provide qualitative information to link in silico predictions to adverse outcomes.
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1431||Serotonin 1A Receptor Agonism||Serotonin 1A Receptor Agonism|
|2||KE||1426||Release of G Proteins||Release of G Proteins|
|3||KE||1429||Inhibition of N-type Ca ion channels||Inhibition of Ca Channels|
|4||KE||1430||Inhibition of neurotransmitter vesicle release||Inhibition of neurotransmitter release|
|5||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 Inhibition of Ca Channels||adjacent||High|
|Inhibition of Ca Channels leads to Inhibition of neurotransmitter release||adjacent||High|
|Inhibition of neurotransmitter release 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 , Gi 3 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 inhibition of N-type Ca ion channel
“activation of 5HT 1A receptors leads to inhibition of N-type Ca channels” SO Ogren 2007
“A ubiquitous pathway is…Gβγ-induced…closing of Ca2+ channels occur mainly in neuroendocrine cells” PR Albert 2001
“the 5HT 1A… couples via Go, but not Gi, to inhibition of L-type Ca2+ channel activation. This coupling presumably occurs via G-beta-gamma subunit interaction with the channel alpha-1 subunit” PR Albert 2001
“In addition, agonist binding to this receptor causes inhibition of N-type Ca-channels” T Adayev 2003
“5-HT1A signaling inhibits L-type voltage-dependent Ca2+ channel through a G-protein-mediated diffusible cytosolic messenger, and by this way abrogate Ca2+ entry into nerve cells” E Lacivita 2008
5-HT 1A receptor activation also inhibits voltage-gated calcium channel activity to reduce calcium entry. 5-HT 1A receptor-mediated inhibition of Ca 2+ currents in dorsal raphe was found to be inhibited by a peptide inhibitor of G protein βγ subunit” Z Chilmonczyk 2015
Inhibition of N-type Ca ion channel leading to inhibition of neurotransmitter vesicle release
“(N-type) Ca2+ channels are known to mediate… presynaptic transmitter release at lamprey synapses” RH Hill 2003
Inhibition of neurotransmitter vesicle release 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
“5-HT 1A receptors are deeply involved in the mechanism of action of antidepressant drugs” P Celada 2003
“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
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.
Hill R.H., Svensson E., Dewael Y., Grillner S. (2003) Eur. J. Neurosci. 18, 2919.
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.