GPCR signaling via cAMP nanodomains

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, mediating essential physiological responses through diverse intracellular signaling pathways. When coupled to Gs or Gi proteins, GPCR modulates the synthesis of 3′-5′-cyclic adenosine monophosphate (cAMP), which governs a wide array of processes, ranging from cellular growth and survival to metabolic regulation. Studies have highlighted that cAMP is not uniformly distributed within cells but instead is compartmentalized into highly localized nanodomains. These nanodomains, mostly regulated by phosphodiesterases (PDEs), play a critical role in enabling signal precision and functional effects that are specific to individual stimuli. GPCRs can initiate distinct cAMP responses based on their localization within the cell, with evidence showing that both receptors resident at the plasma membrane and intracellular receptors—including endosomal, Golgi, and nuclear GPCRs—elicit unique cAMP signaling profiles. This review examines the mechanisms underlying GPCR signaling through cAMP nanodomains. We focus on the role of PDE-mediated cAMP degradation in shaping local cAMP signals, the emerging views on mechanisms that may contribute to signal compartmentalization, and the role of intracellular membrane compartments. By exploring these aspects, we aim to highlight the complexity of GPCR signaling networks and illustrate some of the implications for the regulation of cellular function.