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Norepinephrine Modulates the Motility of Resting and Activated Microglia via Different Adrenergic Receptors
Open accessAbstract
Microglia, the resident immune cells of the central nervous system (CNS), monitor the brain for disturbances of tissue homeostasis by constantly moving their fine processes. Microglia respond to tissue damage through activation of ATP/ADP receptors followed by directional process extension to the damaged area. A common feature of several neurodegenerative diseases is the loss of norepinephrine, which might contribute to the associated neuroinflammation. We carried out a high resolution analysis of the effects of norepinephrine (NE) on microglial process dynamics in acute brain slices from mice that exhibit microglia-specific enhanced green fluorescent protein expression. Bath application of NE to the slices resulted in significant process retraction in microglia. Analysis of adrenergic receptor expression with quantitative PCR indicated that resting microglia primarily express β 2 receptors but switch expression to α 2A receptors under proinflammatory conditions modeled by LPS treatment. Despite the differential receptor expression, NE caused process retraction in both resting and LPS-activated microglia cultured in the gelatinous substrate Matrigel in vitro . The use of subtype-selective receptor agonists and antagonists confirmed the involvement of β 2 receptors in mediating microglial process dynamics in resting cells and α 2A receptors in activated cells. Co-application of NE with ATP to resting microglia blocked the ATP-induced process extension and migration in isolated microglia, and β 2 receptor antagonists prolonged ATP effects in brain slice tissues, suggesting the presence of cross-talk between adrenergic and purinergic signaling in microglia. These data show that the neurotransmitter NE can modulate microglial motility, which could affect microglial functions in pathogenic situations of either elevated or reduced NE levels. Background: Microglia respond to cell death by extending their processes toward ATP released at the site of damage. Results: Norepinephrine induces process retraction in resting and activated microglia through β 2 and α 2A receptors, respectively. Conclusion: Norepinephrine alters the ability of microglia to respond to ATP. Significance: Adrenergic receptor signaling might alter the ability of microglia to detect and respond to tissue damage in vivo .
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“guanfacine’s protective effects may involve anti-inflammatory actions through α2A-AR on glia”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Gyoneva & Traynelis, 2013
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“α2A-AR stimulation deactivates microglia and thus has anti-inflammatory actions.”
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“Microglia and astrocytes are activated by β-AR stimulation, while activated microglia are deactivated by α2A-AR stimulation102.”
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“Microglia and astrocytes are activated by β-AR stimulation, while activated microglia are deactivated by α2A-AR stimulation102.”
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Metadata
- Authors
- Gyoneva, S., & Traynelis, S. F.
- Affiliations
- Emory University (US)
- Corresponding author
- Gyoneva, Stefka
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 288
- Issue
- 21
- Pages
- 15291-15302
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3663549
- OpenAlex
- W2008810019
- Cited by
- 204
- References
- 64
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 27 · 2023: 21 · 2022: 20 · 2021: 10 · 2020: 19 · 2019: 25 · 2018: 17 · 2017: 8 · 2016: 14 · 2015: 14 · 2014: 5 · 2013: 2
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM008602)
- National Institute of Neurological Disorders and Stroke (F31NS076215, P50NS071669)
- National Institute of Environmental Health Sciences (5T32ES12870, T32ES012870)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- norepinephrine, microglia, microglial motility, adrenergic receptors, beta2-adrenergic receptor, alpha2A-adrenergic receptor, purinergic signaling, microglial activation, lipopolysaccharide, neuroinflammation, neurodegenerative diseases
- MeSH terms
- Adenosine Triphosphate, Adrenergic alpha-Agonists, Animals, Cell Movement, Cells, Cultured, Mice, Transgenic, Norepinephrine, Signal Transduction, Microglia, Receptors, Adrenergic, alpha-2, Receptors, Adrenergic, beta-2, Mice
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