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AOP: 235

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Serotonin 1A Receptor Agonism leading to Anti-depressant Activity via K Channel Opening

Short name

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Serotonin 1A Receptor Agonism to Anti-depressant Activity via K Channel

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Handbook Version v1.0

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Timothy E H Allen, University of Cambridge, teha2@cam.ac.uk

Point of Contact

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Timothy Allen (email point of contact)

Contributors

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Timothy Allen

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page	Revision Date/Time
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

Abstract

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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

Context

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Strategy

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Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1431

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

1432

Anti-depressant Activity

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

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

Network View

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Prototypical Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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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

Neuronal Location

“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

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Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

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Known Modulating Factors

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

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.