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