Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling
Open accessAbstract
G protein-coupled receptors (GPCRs) relay extracellular stimuli into specific cellular functions. Cells express many different GPCRs, but all these GPCRs signal to only a few second messengers such as cAMP. It is largely unknown how cells distinguish between signals triggered by different GPCRs to orchestrate their complex functions. Here, we demonstrate that individual GPCRs signal via receptor-associated independent cAMP nanodomains (RAINs) that constitute self-sufficient, independent cell signaling units. Low concentrations of glucagon-like peptide 1 (GLP-1) and isoproterenol exclusively generate highly localized cAMP pools around GLP-1- and β 2-adrenergic receptors, respectively, which are protected from cAMP originating from other receptors and cell compartments. Mapping local cAMP concentrations with engineered GPCR nanorulers reveals gradients over only tens of nanometers that define the size of individual RAINs. The coexistence of many such RAINs allows a single cell to operate thousands of independent cellular signals simultaneously, rather than function as a simple "on/off" switch.
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Rise in cAMP activates PKA, which can inhibit NF-κB signaling, reducing production of inflammatory factors such as iNOS and other inflammation-related proteins.
“The rise in cAMP further activates PKA, which can inhibit the NF-κB signaling pathway, reducing the production of inflammatory factors such as iNOS and other inflammation-related proteins.12,340,341”
From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [340]
The section on GLP-1 receptor nanodomain signaling reports that a local rise in cAMP produces local PKA activity. The Discussion likewise links receptor-associated cAMP to PKA activity. Neither passage establishes that PKA inhibits NF-κB or reduces iNOS and other inflammatory proteins; a search for those terms found no supporting passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredWhen GLP-1 binds to GLP-1R, it activates cAMP signaling, leading to increased cAMP levels.
“When GLP-1 binds to GLP-1R, it activates the cAMP signaling pathway, leading to increased cAMP levels.1,340”
From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [340]
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Glucagon-like peptide-1 receptor: mechanisms and advances in therapy
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- Authors
- Anton, S. E., Kayser, C., Maiellaro, I., Nemec, K., Möller, J., Koschinski, A., Zaccolo, M., Annibale, P., Falcke, M., Lohse, M. J., & Bock, A.
- Affiliations
- Max Delbrück Center (DE)
- University of Nottingham (GB)
- University of Oxford (GB)
- University of St Andrews (GB)
- Corresponding author
- Lohse, Martin J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2022-03
- Volume
- 185
- Issue
- 7
- Pages
- 1130-1142.e11
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W4220714894
- Cited by
- 186
- References
- 69
- Citations by year
- 2026: 22 · 2025: 50 · 2024: 44 · 2023: 50 · 2022: 20
- FWCI
- 13.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 395 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Repository@Nottingham (University of Nottingham) (acceptedVersion, other-oa)
- St Andrews Research Repository (St Andrews Research Repository) (acceptedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by-nc-nd)
- Funders
- British Heart Foundation (PG/15/5/31110, RG/17/6/32944)
- Deutsche Forschungsgemeinschaft (SFB 688)
- Elitenetzwerk Bayern
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Keywords
- G protein-coupled receptors, spatiotemporal signaling, GLP-1 receptor, beta2-adrenergic receptor, cAMP signaling, cAMP gradients, second messengers, signaling specificity
- MeSH terms
- Cyclic AMP, Cell Physiological Phenomena, Second Messenger Systems, Signal Transduction, Receptors, Adrenergic, beta-2, Receptors, G-Protein-Coupled, Glucagon-Like Peptide 1
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