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AOP: 236

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 Ca Channel Inhibition

Short name

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

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v1.0

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

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
Inhibition of N-type Ca ion channels	June 23, 2017 06:50
Inhibition of neurotransmitter vesicle release	June 27, 2023 17:42
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

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

A measurable event within a specific biological level of organisation. More help

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	1429	Inhibition of N-type Ca ion channels	Inhibition of Ca Channels
KE	1430	Inhibition of neurotransmitter vesicle release	Inhibition of neurotransmitter release

1432

Anti-depressant Activity

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

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

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

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

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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

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.

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.