Factors Determining the Specificity of Signal Transduction by Guanine Nucleotide-binding Protein-coupled Receptors

Abstract

Cell to cell communication by many hormones and neurotransmitters involves three major entities: recep-tor (R), G-protein (G), and effector molecule (E). Plas-ticity in this system is conferred by the existence of each entity as isoforms or closely related subtypes that are expressed in a tissue-specific and developmentally regulated manner. Factors that determine signal spec-ificity in this system are poorly understood. Such fac-tors include the relative affinity and stoichiometry of R-G or G-E and the possible colocalization of R-G-E in cellular microdomains. Utilizing the az-adrenergic receptor (aZ-AR) system as a representative subfamily of this class of signal transducers, we determined the relative importance of these factors. By analysis of R-G coupling in mammalian cells cotransfected with az-AR genes and G, cDNA, we demonstrate preferential coupling between an m-AR subtype and Go. Our data implicate R-G affinity as an important determinant of signal transduction specificity and indicate that a crit-ical level of G, is required for coupling. This report indicates the utility of R-G cotransfection in mamma-lian cells as a " natural environment model " to charac-terize events occurring at the R-G and G-E interface. az-Adrenergic receptor (aZ-AR)' activation in different tis-sues can elicit a variety of cell responses (1,2), many of them pertussis toxin (PT)-sensitive, indicating receptor coupling with a specific class of G-proteins (Gil,z,S or Go). However, in many cases, neither the receptor subtype (3-6) nor the G-protein involved is known.