New Determinants of Receptor-Effector Coupling: Trafficking and Compartmentation in Membrane Microdomains
"The multicomponent modular nature of G protein-coupled receptor (GPCR) systems provides cells with numerous potential combinations by which to transduce signals. A typical cell appears to express a dozen or so different GPCR genes (of which nearly a thousand exist in the human genome), several different combinations of G protein subunits and multiple isoforms of effector molecules that can be activated by each type of G protein. The differential expression of these various proteins allows modulation of signals at many levels, resulting in messages that are customized for a specific cell type. Much of the effort to understand signaling via these complicated cellular networks has focused on defining the linear progression of molecular interactions involved in a given pathway. This approach has yielded important information regarding the types of pathways (i.e., the class of G protein and cognate downstream effectors) that are characteristically activated by a given receptor and, thereby, the types of alterations in cell function that are elicited. The current dogma is that high-affinity protein-protein interactions determine the identity of the G protein with which a particular GPCR interacts and, in turn, dictates the biochemical pathways that are activated by that receptor. However, numerous observations in various cells and tissues have indicated that different receptors coupling to the same G protein in a single cell can elicit different biochemical or cellular responses (Hayes and Brunton, 1982; Buxton and Brunton, 1983; Harper et al., 1985; Graeser and Neubig, 1993; Xu et al., 1996; Steinberg and Brunton, 2001). The classical view that GPCR signal transduction is one-dimensional cannot readily account for these observations. Two additional dimensions must be incorporated into our conceptual models: 1) the compartmentation of receptors and effector molecules in subcellular compartments and microdomains of the plasma membrane, and 2) the movement, or translocation, of receptors between cellular compartments (trafficking)."
Rennolds S Ostrom. New determinants of receptor-effector coupling: trafficking and compartmentation in membrane microdomains. Mol Pharmacol,61(3):473-6, 2002.
American Society for Pharmacology and Experimental Therapeutics (ASPET)