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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Pages (from-to)1130-1142
Number of pages24
JournalCell
Volume185
Issue number7
Early online date10 Mar 2022
DOIs
Publication statusPublished - 31 Mar 2022

Keywords

  • G protein-coupled receptors
  • cAMP
  • Compartmentation
  • Cell signaling
  • FRET
  • Biosensors
  • Nanodomains
  • Spatiotemporal signaling
  • Diffusion
  • GLP-1

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