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

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

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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
Cataia Ives   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Timothy Allen
  • Cataia Ives

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Not under active development Under Development
This AOP was last modified on July 16, 2022 18:37

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

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 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

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)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
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 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)

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

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

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

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, 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

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

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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. (2003Biochim. Biophys. Acta-Molecular Cell Res. 1640, 8.

Albert P.R., Tiberi M. (2001Trends 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. (2015Int. J. Mol. Sci. 16, 18474.

Hensler J.G. (2003Life 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. (2007Physiol. Behav. 92, 172.