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

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 beta(2)-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.

Automated summary

Cells use independent cAMP nanodomains to send different signals, which form self-sufficient cell signaling units. Each nanodomain contains a highly localized cAMP pool that is protected from other receptors and cell compartments. The gradients of local cAMP concentrations define the size of each individual nanodomain. The coexistence of many such nanodomains allows a single cell to operate multiple independent cellular signals simultaneously.