The R7 RGS protein family: multi-subunit regulators of neuronal G protein signaling

Abstract

G protein-coupled receptor signaling pathways mediate the transmission of signals from the extracellular environment to the generation of cellular responses, a process that is critically important for neurons and neurotransmitter action. The ability to promptly respond to rapidly changing stimulation requires timely inactivation of G proteins, a process controlled by a family of specialized proteins known as regulators of G protein signaling (RGS). The R7 group of RGS proteins (R7 RGS) has received special attention due to their pivotal roles in the regulation of a range of crucial neuronal processes such as vision, motor control, reward behavior, and nociception in mammals. Four proteins in this group, RGS6, RGS7, RGS9, and RGS11, share a common molecular organization of three modules: (i) the catalytic RGS domain, (ii) a GGL domain that recruits G beta(5), an outlying member of the G protein beta subunit family, and (iii) a DEP/DHEX domain that mediates interactions with the membrane anchor proteins R7BP and R9AP. As heterotrimeric complexes, R7 RGS proteins not only associate with and regulate a number of G protein signaling pathway components, but have also been found to form complexes with proteins that are not traditionally associated with G protein signaling. This review summarizes our current understanding of the biology of the R7 RGS complexes including their structure/functional organization, protein-protein interactions, and physiological roles.

Figure 1. Organization of trimeric complexes between R7 RGS proteins and their subunits: R7BP/R9AP and Gβ₅

R7 RGS proteins consist of three functional modules. The N-terminal DEP (Disheveled, EGL-10, Pleckstrin) and DHEX (DEP helical extension) domains mediate binding to the membrane anchors R7BP and R9AP. The central GGL (G Protein gamma-like) domain forms a complex with the Gβ₅ (G protein β subunit, type 5). The C-terminal RGS (regulator of G protein signaling) domain mediates transient association with Gα-GTP subunits, during which GTP hydrolysis is stimulated. In addition to the GGL domain, Gβ₅ also associates with the DEP/DHEX module.

Figure 2. Membrane anchors R7BP and R9AP share structural similarities with SNARE proteins

Schematic representation of R7BP and R9AP domain compositions in comparison with three canonical SNARE proteins. Green boxes represent the alpha helical regions, blue boxes indicate conservative coiled-coil domains that participate in SNARE complex formation, yellow boxes indicate transmembrane regions and red lines indicate sites of membrane attachment.