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, proteolytic fragments of GPCRs capable of ligand-independent 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 differences 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
Edward J
EJ
Department of Medicine, University of California, San Francisco, California, USA. edward.goetzl@ucsf.edu
D000818:Animals; D002467:Cell Nucleus / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D008024:Ligands; D043562:Receptors, G-Protein-Coupled