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Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling

Anton, Selma E.; Kayser, Charlotte; Maiellaro, Isabella; Nemec, Katarina; Möller, Jan; Koschinski, Andreas; Zaccolo, Manuela; Annibale, Paolo; Falcke, Martin; Lohse, Martin J.; Bock, Andreas

Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling Thumbnail


Authors

Selma E. Anton

Charlotte Kayser

Katarina Nemec

Jan Möller

Andreas Koschinski

Manuela Zaccolo

Paolo Annibale

Martin Falcke

Martin J. Lohse

Andreas Bock



Abstract

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 β2-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.

Journal Article Type Article
Acceptance Date Feb 9, 2022
Online Publication Date Mar 15, 2022
Publication Date Mar 31, 2022
Deposit Date Mar 20, 2022
Publicly Available Date Mar 16, 2023
Journal Cell
Print ISSN 0092-8674
Electronic ISSN 1097-4172
Publisher Elsevier BV
Peer Reviewed Peer Reviewed
Volume 185
Issue 7
Pages 1130-1142.e11
DOI https://doi.org/10.1016/j.cell.2022.02.011
Keywords General Biochemistry, Genetics and Molecular Biology
Public URL https://nottingham-repository.worktribe.com/output/7641552
Publisher URL https://www.cell.com/cell/fulltext/S0092-8674(22)00191-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS009286742200191X%3Fshowall%3Dtrue

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