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

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CELL_D_21_01363_R3.pdf (1.829Mb)
Date
31/03/2022
Author
Anton, Selma E.
Kayser, Charlotte
Maiellaro, Isabella
Nemec, Katarina
Moeller, Jan
Koschinski, Andreas
Zaccolo, Manuela
Annibale, Paolo
Falcke, Martin
Lohse, Martin J.
Bock, Andreas
Keywords
G protein-coupled receptors
cAMP
Compartmentation
Cell signaling
FRET
Biosensors
Nanodomains
Spatiotemporal signaling
Diffusion
GLP-1
QH301 Biology
QC Physics
NDAS
AC
MCC
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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.
Citation
Anton , S E , Kayser , C , Maiellaro , I , Nemec , K , Moeller , J , Koschinski , A , Zaccolo , M , Annibale , P , Falcke , M , Lohse , M J & Bock , A 2022 , ' Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling ' , Cell , vol. 185 , no. 7 , pp. 1130-1142 . https://doi.org/10.1016/j.cell.2022.02.011
Publication
Cell
Status
Peer reviewed
DOI
https://doi.org/10.1016/j.cell.2022.02.011
ISSN
0092-8674
Type
Journal article
Rights
Copyright © 2022 Elsevier Inc. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1016/j.cell.2022.02.011.
Description
Funding: A.B., P.A., and M.J.L. acknowledge funding by the Deutsche Forschungsgemeinschaft (DFG) (German Research Foundation) through SFB1423, project number 421152132, subproject C03 (P.A. and M.J.L.) and subproject C05 (A.B.), and through SFB688, subproject B08 (M.J.L.). This work was supported by the Elite Network of Bavaria, Receptor Dynamics program (to M.J.L.). S.E.A. and J.M. were members of this program. I.M. is an Anne McLaren Research Fellow. This work was supported by the British Heart Foundation PG/15/5/31110 and RG/17/6/32944 (to M.Z.).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/27149

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