Norepinephrine activates β1‐adrenergic receptors at the inner nuclear membrane in astrocytes

Norepinephrine exerts powerful influences on the metabolic, neuroprotective and immunoregulatory functions of astrocytes. Until recently, all effects of norepinephrine were believed to be mediated by receptors localized exclusively to the plasma membrane. However, recent studies in cardiomyocytes ha...

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Bibliographic Details
Published in:Glia 2022-09, Vol.70 (9), p.1777-1794
Main Authors: Benton, Kelsey C., Wheeler, Daniel S., Kurtoglu, Beliz, Ansari, Mahshid Bagher Zadeh, Cibich, Daniel P., Gonzalez, Dante A., Herbst, Matthew R., Khursheed, Saema, Knorr, Rachel C., Lobner, Doug, Maglasang, Jenree G., Rohr, Kayla E., Taylor, Analisa, Twining, Robert C., Witt, Paul J., Gasser, Paul J.
Format: Article
Language:English
Subjects:
adrenergic receptor
Adrenergic receptors
Astrocytes
Biosensors
Cardiomyocytes
Catecholamine
Catecholamines
Central nervous system
Fluorescence
G protein‐coupled receptors
Golgi apparatus
Immunofluorescence
Immunoregulation
Kinases
Membranes
Metabolism
monoamine transporter
Neuroprotection
Norepinephrine
Norepinephrine transporter
Nuclear membranes
Nuclei (cytology)
nucleus
Oct-4 protein
Organic cation transporter
Protein kinase A
Receptors (physiology)
Signaling
subcellular localization
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Summary:Norepinephrine exerts powerful influences on the metabolic, neuroprotective and immunoregulatory functions of astrocytes. Until recently, all effects of norepinephrine were believed to be mediated by receptors localized exclusively to the plasma membrane. However, recent studies in cardiomyocytes have identified adrenergic receptors localized to intracellular membranes, including Golgi and inner nuclear membranes, and have shown that norepinephrine can access these receptors via transporter‐mediated uptake. We recently identified a high‐capacity norepinephrine transporter, organic cation transporter 3 (OCT3), densely localized to outer nuclear membranes in astrocytes, suggesting that adrenergic signaling may also occur at the inner nuclear membrane in these cells. Here, we used immunofluorescence and western blot to show that β1‐adrenergic receptors are localized to astrocyte inner nuclear membranes; that key adrenergic signaling partners are present in astrocyte nuclei; and that OCT3 and other catecholamine transporters are localized to astrocyte plasma and nuclear membranes. To test the functionality of nuclear membrane β1‐adrenergic receptors, we monitored real‐time protein kinase A (PKA) activity in astrocyte nuclei using a fluorescent biosensor. Treatment of astrocytes with norepinephrine induced rapid increases in PKA activity in the nuclear compartment. Pretreatment of astrocytes with inhibitors of catecholamine uptake blocked rapid norepinephrine‐induced increases in nuclear PKA activity. These studies, the first to document functional adrenergic receptors at the nuclear membrane in any central nervous system cell, reveal a novel mechanism by which norepinephrine may directly influence nuclear processes. This mechanism may contribute to previously described neuroprotective, metabolic and immunoregulatory actions of norepinephrine. Main Points β1‐adrenergic receptors and their signaling partners are localized to astrocyte nuclei. Norepinephrine‐induced activation of nuclear β1 receptors leads to rapid increases in nuclear PKA activity and requires transmembrane catecholamine transport.
ISSN:0894-1491
1098-1136
DOI:10.1002/glia.24219