cAMP signaling: a remarkably regional affair

Cell signaling occurs in the restricted confines of highly organized intracellular signaling nanodomains.Receptor-associated independent cAMP nanodomains (RAINs) drive local cAMP synthesis and localized signaling.Optical mapping of local cAMP pools has defined local cAMP nanodomains due to buffered diffusion of second messengers.G protein-coupled receptor (GPCR) signaling at subcellular membrane compartments generates isolated intracellular pools of cAMP that drive unique cellular functions.A-kinase anchoring protein (AKAP)-signaling islands regionally distributed throughout the cell potentiate individual protein kinase A (PKA) phosphorylation events at the nanometer scale. Louis Pasteur once famously said ‘in the fields of observation chance favors only the prepared mind’. Much of chance is being in the right place at the right time. This is particularly true in the crowded molecular environment of the cell where being in the right place is often more important than timing. Although Brownian motion argues that enzymes will eventually bump into substrates, this probability is greatly enhanced if both molecules reside in the same subcellular compartment. However, activation of cell signaling enzymes often requires the transmission of chemical signals from extracellular stimuli to intracellular sites of action. This review highlights new developments in our understanding of cAMP generation and the 3D utilization of this second messenger inside cells. Louis Pasteur once famously said ‘in the fields of observation chance favors only the prepared mind’. Much of chance is being in the right place at the right time. This is particularly true in the crowded molecular environment of the cell where being in the right place is often more important than timing. Although Brownian motion argues that enzymes will eventually bump into substrates, this probability is greatly enhanced if both molecules reside in the same subcellular compartment. However, activation of cell signaling enzymes often requires the transmission of chemical signals from extracellular stimuli to intracellular sites of action. This review highlights new developments in our understanding of cAMP generation and the 3D utilization of this second messenger inside cells.