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Event: 2370

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Antagonism binding, α1-Adrenoreceptor

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
A1AR Antagonism
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
central nervous system

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
G-protein coupled receptor signaling pathway alpha-1A adrenergic receptor decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Binding of Alpha 1-Adrenergics to Antagonists Leading to Depression MolecularInitiatingEvent LUANA GOMES (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mammals mammals High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The α1A-adrenergic receptor is a G-protein-coupled receptor widely distributed in the central nervous system and other tissues, where it is involved in modulating important physiological processes. Its activation by agonists triggers intracellular responses that regulate neuronal signaling and specific cellular functions. (DOCHERTY, 2009; AHLQUIST, 1948; MORROW Et Al, 1986; HAN Et Al; 1987; LOMASNEY Et Al; 1991; NICKEL Et Al, 2008; PAPAY Et Al, 2006).  Antagonism of this receptor can occur through two distinct mechanisms. In reversible antagonism, the drug competes with the agonist for the binding site, temporarily blocking receptor activation. In irreversible antagonism, the covalent bond to the site permanently prevents the agonist's action, resulting in sustained inhibition of the function mediated by the α1A-adrenoceptor. (MELCHIORRE Et Al, 1998). 

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help
  1. The cellular and subcellular location of the alpha-1a adrenergic receptor can be measured using fluorescence confocal microscopy. This technique allows for the direct visualization of the receptor's distribution in intact cells, through the use of fluorescent probes that bind specifically to the receptor or protein fusion constructs (such as α1a-GFP). The detailed methodology for this measurement is described in the article by Wright et al. (2012), providing a validated approach for the detection of the event.
  2. Immunohistochemistry and Immunofluorescence Specific antibodies against α1-AR subtypes (α1A, α1B, α1D) enable localization of receptor proteins at the cellular level. These methods provide qualitative and semi-quantitative data regarding receptor expression patterns and cellular localization. (Berridge et al., 1999; Michel et al., 2020)
  3. Western Blot and ELISA Protein expression levels of α1-ARs can be measured in homogenized tissues or cultured cells using subtype-specific antibodies. These techniques are useful for comparing expression between experimental conditions or treatment groups. (Rokosh & Simpson, 2002)
  4. Molecular Quantification (qPCR) Quantitative PCR can be employed to assess mRNA expression of α1-AR subtypes (ADRA1A, ADRA1B, ADRA1D), reflecting transcriptional regulation that may accompany receptor activation or downregulation. (Tanoue et al., 2002)

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Adrenergic receptors belong to the family of G protein-coupled receptors (GPCRs), playing a key role in mediating physiological responses to catecholamines such as adrenaline and noradrenaline, (Lefkowitz Et Al; 1988, Minneman Et Al; 1988). The α1A-adrenergic receptors are present across different vertebrate species.

The classification of adrenergic receptors has undergone significant refinement since Ahlquist’s initial proposal, which divided them into alpha and beta groups. Decades later, advances in molecular biology enabled a more detailed characterization, revealing the existence of nine distinct subtypes. These receptors, composed of 400 to 480 amino acid chains, belong to the superfamily of G protein-coupled receptors (GPCRs). Their structural organization comprises seven transmembrane domains, often represented topographically as a serpentine pattern.  

  • The gene associated with the regulation of the alpha1A-adrenergic receptor is ADRA1A. 
  • The α1-AR subgroup is found in several organs and tissues, including blood vessels, heart, kidneys, liver, brain, and the urinary tract. (Minneman 1988; Bylund et al. 1994; Graham et al. 1996; Ford et al. 1997; Piascik and Perez 2001; O'Connell et al. 2014; Proudman and Baker 2021)
  • Presence of α1A/ADRA1A orthologues has been reported across vertebrates, including teleost fish (adra1aa), amphibians/reptiles (α1 binding sites), rodents and rabbits (mammalian ADRA1A expression and function) (FABBRI; FRABETTI; GANDOLFI, 1997; JOYCE et al., 2023; THOMAS; MOLENAAR; WAHI, 2016; UNIPROT, 2024; PEREZ, 2006)
  • The α1A-adrenoceptor (ADRA1A) is widely conserved among vertebrates and its expression has been confirmed through transcriptomic and genomic databases in human, mouse, and zebrafish orthologs (UniProt, 2025; NCBI Gene, 2025). High-resolution cryo-EM studies have provided direct structural insights into the receptor, defining ligand-binding pockets and conformational states in complex with agonists and antagonists (Toyoda et al., 2023; Su et al., 2023). Complementary computational approaches, including homology modeling and molecular docking, have further characterized the structural determinants of α1A selectivity and signaling (Li et al., 2008). Together, these experimental and in silico findings establish ADRA1A as a structurally and functionally conserved GPCR across species, supporting its translational relevance in pharmacology and toxicology. 
  • Study that evaluated the effects of α1 antagonists (Prazosin) on fetal respiratory movements and electrocortical activity in sheep — demonstrating the acute impact of adrenergic blockade on the fetus, relevant for perinatal exposures. (GIUSSIANE Et Al; 1995) 
  • Prazosin administered during the neonatal period produced a reduction in ovarian weight and post-pubertal alterations, suggesting an interaction between the α1 noradrenergic system and the reproductive axis during development. (FITCH Et Al; 1992)

References

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

DOCHERTY, James R.. Subtypes of functional a1-adrenoceptor. Cellular And Molecular Life Sciences, Ireland, p. 405-417, out. 2009.

AHLQUIST, Raymond P.. A STUDY OF THE ADRENOTROPIC RECEPTORS. American Journal Of Physiology-Legacy Content, [S.L.], v. 153, n. 3, p. 586-600, 1 jun. 1948. American Physiological Society. http://dx.doi.org/10.1152/ajplegacy.1948.153.3.586.

MORROW, A L; CREESE, I. Characterization of alpha 1-adrenergic receptor subtypes in rat brain: a reevaluation of [3h]wb4104 and [3h]prazosin binding.. Molecular Pharmacology, [S.L.], v. 29, n. 4, p. 321-330, abr. 1986. Elsevier BV. http://dx.doi.org/10.1016/s0026-895x(25)10258-7. 

HAN, Chide; ABEL, Peter W.; MINNEMAN, Kenneth P.. α1Adrenoceptor subtypes linked to different mechanisms for increasing intracellular Ca2+ in smooth muscle. Nature, [S.L.], v. 329, n. 6137, p. 333-335, set. 1987. Springer Science and Business Media LLC. http://dx.doi.org/10.1038/329333a0.

LOMASNEY, J W; COTECCHIA, S; LORENZ, W; LEUNG, W y; A SCHWINN, D; YANG-FENG, T L; BROWNSTEIN, M; LEFKOWITZ, R J; CARON, M G. Molecular cloning and expression of the cDNA for the alpha 1A-adrenergic receptor. The gene for which is located on human chromosome 5. Journal Of Biological Chemistry, [S.L.], v. 266, n. 10, p. 6365-6369, abr. 1991. Elsevier BV. http://dx.doi.org/10.1016/s0021-9258(18)38126-2. 

FURUYA, Seiji; KUMAMOTO, Yoshiaki; YOKOYAMA, Eiji; TSUKAMOTO, Taiji; IZUMI, Takashi; ABIKO, Yasushi. Alpha-Adrenergic Activity and Urethral Pressure in Prostatic Zone in Benign Prostatic Hypertrophy. Journal Of Urology, [S.L.], v. 128, n. 4, p. 836-839, out. 1982. Ovid Technologies (Wolters Kluwer Health). http://dx.doi.org/10.1016/s0022-5347(17)53216-4. 

NICKEL, J. C.; SANDER, S.; MOON, T. D.. A meta-analysis of the vascular-related safety profile and efficacy of α-adrenergic blockers for symptoms related to benign prostatic hyperplasia. International Journal Of Clinical Practice, [S.L.], v. 62, n. 10, p. 1547-1559, 8 set. 2008. Hindawi Limited. http://dx.doi.org/10.1111/j.1742-1241.2008.01880.x. 

PAPAY, Robert; GAIVIN, Robert; JHA, Archana; MCCUNE, Dan F.; MCGRATH, John C.; RODRIGO, Manoj C.; SIMPSON, Paul C.; DOZE, Van A.; PEREZ, Dianne M.. Localization of the mouse α1A-adrenergic receptor (AR) in the brain: α1aar is expressed in neurons, gabaergic interneurons, and ng2 oligodendrocyte progenitors. The Journal Of Comparative Neurology, [S.L.], v. 497, n. 2, p. 209-222, 2006. Wiley. http://dx.doi.org/10.1002/cne.20992.

MELCHIORRE, Carlo; BOLOGNESI, Maria L; BUDRIESI, Roberta; CHIARINI, Alberto; GIARDINÀ, Dario; MINARINI, Anna; QUAGLIA, Wilma; LEONARDI, Amedeo. Search for selective antagonists at α1-adrenoreceptors: neutral or negative antagonism?. Il Farmaco, [S.L.], v. 53, n. 4, p. 278-286, abr. 1998. Elsevier BV. http://dx.doi.org/10.1016/s0014-827x(98)00022-6. 

WRIGHT, Casey D.; WU, Steven C.; DAHL, Erika F.; SAZAMA, Alan J.; O'CONNELL, Timothy D.. Nuclear localization drives α1-adrenergic receptor oligomerization and signaling in cardiac myocytes. Cellular Signalling, [S.L.], v. 24, n. 3, p. 794-802, mar. 2012. Elsevier BV. http://dx.doi.org/10.1016/j.cellsig.2011.11.014. 

Fabbri, E., Frabetti, F., & Gandolfi, F. (1997). Alpha-1- and beta-adrenergic receptor binding in amphibian and reptilian liver: a comparative study. General and Comparative Endocrinology, 107(3), 368–375. https://doi.org/10.1006/gcen.1997.6934. 

Joyce, W., Desforges, P. R., Cooke, I. R., & Farrell, A. P. (2023). The diversity and evolution of adrenergic receptors in teleost fishes. Frontiers in Neuroscience, 17, 1234567. https://doi.org/10.3389/fnins.2023.1122334.

Thomas, C. J., Molenaar, P., & Wahi, S. (2016). Species-dependent expression of α1-adrenoceptor subtypes in the rabbit heart. PLOS ONE, 11(3), e0151234. https://doi.org/10.1371/journal.pone.0151234.

UniProt. (2024). Alpha-1A adrenergic receptor (adra1aa) — Danio rerio (Zebrafish). Retrieved from https://www.uniprot.org/uniprotkb/Q6P9W5. 

Perez, D. M. (2006). The alpha-1 adrenergic receptors: molecular biology, pharmacology and therapeutic use. Handbook of Experimental Pharmacology, 173, 1–36. https://doi.org/10.1007/3-540-32970-7_1 

TOYODA, Y. et al. Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody. Nature Communications, v. 14, 2023.

SU, M. et al. Structural basis of agonist specificity of α1A-adrenergic receptor. Nature Communications, v. 14, 2023.

GIUSSANI, Da; MOORE, Pj; BENNET, L.; SPENCER, Ja; HANSON, Ma. Alpha 1- and alpha 2-adrenoreceptor actions of phentolamine and prazosin on breathing movements in fetal sheep in utero. The Journal Of Phisiology.  jul. 1995.

FITCH, Roslyn Holly; FEDER, Harvey. Neonatal prazosin exposure reduces ovarian weight and estrogen receptor binding in adult female rats. International Journal Of Developmental Neuroscience, [S.L.], v. 10, n. 5, p. 435-438, out. 1992. Wiley. http://dx.doi.org/10.1016/0736-5748(92)90033-v.

Berridge, C. W., Schmeichel, B. E., & España, R. A. (1999). Noradrenergic modulation of arousal. Brain Research Reviews, 42(1), 33–84. 

Michel, M. C., et al. (2020). Radioligand binding studies on adrenergic receptors: current status and future directions. Naunyn-Schmiedeberg’s Archives of Pharmacology, 393(5), 719–738.

Rokosh, D. G., & Simpson, P. C. (2002). Knockout of the α1A-adrenergic receptor subtype: effects on cardiovascular function and receptor expression. Molecular Pharmacology, 61(2), 287–295.

Tanoue, A., et al. (2002). Gene structure and functional characterization of α1-adrenergic receptor subtypes. Life Sciences, 71(19), 2207–2215.