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Cited by 1Extracellular vesicles in diseaseMicroRNA in disease regulationReceptor Mechanisms and Signaling

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Specific GPCRs elicit unique extracellular vesicle miRNA array signatures

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Shi, Xiao, Palumbo, Michelle C, Benware, Sheila, Wiedrick, Jack, Markwardt, Sheila, Janowsky, Aaron J·2026·eLife
DOI 10.7554/elife.107865PMC PMC13004594

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Abstract

All cells secrete extracellular vesicles (EVs) containing nucleic acid cargo, including microRNAs (miRNAs), that regulate the function of receiving cells. G protein-coupled receptors (GPCRs) affect intracellular function via multiple signaling cascades. However, the mechanisms of GPCR intercellular signaling through EV miRNA activity remain unknown. Human U2 osteosarcoma cells expressing native GPCRs were used to selectively stimulate distinct G protein signaling cascades (Gα i , Gα q , Gα 12/13 , and β-arrestin) by members of specific receptor subclasses, including the adenosine receptor A1 (ADORA1), the histamine receptor H1 (HRH1), the frizzled class receptor 4 (FZD4), and the atypical chemokine receptor 3 (ACKR3), respectively. We hypothesized that stimulation of specific classes of GPCRs would cause the release of EVs containing miRNAs with receptor-specific up- or downregulated expression, affecting unique pathological downstream signaling cascades. Receptor-specific agonists dose-dependently increased respective signaling cascade intermediates. We found no change in the quantity of EVs (~200 nm diameter), but there were distinct EV miRNA signatures following stimulation of GPCRs. Network analyses of differentially expressed miRNA and their predicted targets validated the linkage between specific receptors and cell function and pathological states. The data can be used to reverse engineer mechanisms involving EV miRNAs for various physiological and pathological processes. GPCRs are major pharmacological targets, so understanding the mechanisms that stimulate or inhibit GPCR-mediated changes in extracellular miRNA signatures could improve long- and short-term therapeutic and unwanted drug effects.

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Metadata

Authors
Shi, X., Palumbo, M. C., Benware, S., Wiedrick, J., Markwardt, S., & Janowsky, A. J.
Affiliations
  • Portland VA Medical Center (US)
  • Oregon Health & Science University (US)
Corresponding author
Shi, Xiao
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2026-03-20
Volume
14
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.107865
PMC
PMC13004594
OpenAlex
W7139934211
Cited by
1
References
4
Citations by year
2026: 1
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
Funders
  • National Institute on Drug Abuse (ADA 12013, T32AG055378-06)
  • United States Food and Drug Administration (CDER-20-I-0546)
  • Drug Enforcement Administration (D-15-0D-002)
  • United States Department of Veterans Affairs (1IK6BX005754)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
G protein-coupled receptors, extracellular vesicles, microRNA, intercellular communication, Gαi signaling, Gαq signaling, beta-arrestin, adenosine A1 receptor, histamine H1 receptor, FZD4, CXCR7, osteosarcoma cells, miRNA target networks

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