Mechanisms of dominant negative G-protein α subunits

Abstract

G-protein-coupled receptors (GPCRs) represent the largest class of membrane proteins and are the targets of 25-50% of drugs currently on the market. Dominant negative mutant Gα subunits of heterotrimeric G-proteins have been extensively utilized to delineate G-protein signaling pathways and represent a promising new tool to study GPCR-dependent signaling in the CNS. There are different regions in various types of Gα sub-units in which mutations can give rise to a dominant negative phenotype. Such a mutant Gα would compete with wild-type Gα for binding to other proteins involved in the G-protein cycle and either block or reduce the response caused by wild-type Gα. To date, there are three different mechanisms described for dominant negative Gα subunits: sequestration of the Gβγ subunits, sequestration of the activated GPCR by the heterotrimeric complex, and sequestration of the activated GPCR by nucleotide-free Gα. This review focuses on the development of dominant negative Gα subunits, the different mechanisms used by various mutant Gα subunits, and potential structural changes underlying the dominant negative effects. © 2007 Wiley-Liss, Inc.