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

Item Type:Article
Title:Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling
Creators Name:Anton, S.E. and Kayser, C. and Maiellaro, I. and Nemec, K. and Möller, J. and Koschinski, A. and Zaccolo, M. and Annibale, P. and Falcke, M. and Lohse, M.J. and Bock, A.
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 β(2)-adrenergic receptors, respectively, which are protected from cAMP originating from other receptors and cell compartments. Mapping local cAMP concentrations with engineered GPCRnanorulers 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.
Keywords:G Protein-Coupled Receptors, cAMP, Compartmentation, Cell Signaling, FRET, Biosensors, Nanodomains, Spatiotemporal Signaling, Diffusion, GLP-1
Source:Cell
ISSN:0092-8674
Publisher:Cell Press
Volume:185
Number:7
Page Range:1130-1142.e11
Date:31 March 2022
Official Publication:https://doi.org/10.1016/j.cell.2022.02.011
PubMed:View item in PubMed

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