Diverse pathways for nuclear signaling by G protein‐coupled receptors and their ligands

Recent realization that plasma membrane G protein‐coupled receptors (GPCRs) may translocate and establish ligand‐responsive signaling complexes in other cellular structures has motivated studies of site‐specific differences in transductional pathways. GPCRs and their ligands may signal transcription and other nuclear events by two basic mechanisms. The first consists of GPCR‐complex activation of messengers that enter the nucleus and there initiate cell‐modifying processes without the GPCR leaving the plasma membrane. The second encompasses entry into the nuclear membranes or matrix of either GPCR ligands, which bind to non‐GPCR nuclear signaling proteins, proteo‐lytic fragments of GPCRs capable of ligand‐indepen‐dent signaling, or intact GPCRs with transduction‐competent factors that directly initiate or regulate transcriptional events. With the second mechanism, often concurrent down‐regulation of plasma membrane GPCRs terminates signaling from the cell‐surface and moves it into the nuclear domain. Site‐dependent dif‐ferences in signals from the same GPCR provide potentials for unique cellular abnormalities attributable to defective intracellular movement and distribution of a GPCR, site‐specific alterations in ligand concentration, and limited intracellular bioavailability of pharmacological agents that can interact specifically with both nuclear and plasma membrane forms of a GPCR. Goetzl, E. J. Diverse pathways for nuclear signaling by G Protein‐coupled receptors and their ligands. FASEB J. 21, 638–642 (2007)