Insights into G Protein Structure, Function, and Regulation

Abstract

In multicellular organisms from Caenorhabditis elegans to Homo sapiens, the maintenance of homeostasis is dependent on the continual flow and processing of information through a complex network of cells. Moreover, in order for the organism to respond to an ever-changing environment, intercellular signals must be transduced, amplified, and ultimately converted to the appropriate physiological response. The resolution of the molecular events underlying signal response and integration forms the basis of the signal transduction field of research. An evolutionarily highly conserved group of molecules known as heterotrimeric guanine nucleotide-binding proteins (G proteins) are key determinants of the specificity and temporal characteristics of many signaling processes and are the topic of this review. Numerous hormones, neurotransmitters, chemokines, local mediators, and sensory stimuli exert their effects on cells by binding to heptahelical membrane receptors coupled to heterotrimeric G proteins. These highly specialized transducers can modulate the activity of multiple signaling pathways leading to diverse biological responses. In vivo, specific combinations of G alpha- and G beta gamma-subunits are likely required for connecting individual receptors to signaling pathways. The structural determinants of receptor-G protein-effector specificity are not completely understood and, in addition to involving interaction domains of these primary acting proteins, also require the participation of scaffolding and regulatory proteins.

Association of the C825T polymorphism in the GNB3 gene with obesity and metabolic phenotypes in a Taiwanese population

“…The GNB3 gene encodes the beta 3 subunit of heterotrimeric G-proteins, which are key components of intracellular signal transduction between receptors and intracellular effectors virtually in all cells of the body (Cabrera-Vera et al 2003). A common single nucleotide polymorphism (SNP), rs5443 (C825T), located on exon 10 of the GNB3 gene has received much attention.…”

Rapid-mix flow cytometry measurements of subsecond regulation of G protein-coupled receptor ternary complex dynamics by guanine nucleotides

“…The most significant aspects of our present data show that: a) the fastest step associated with ternary complex disassembly is the departure of the receptor from the Gα subunit. b) On the biologically relevant time scale, the hetrotrimeric subunits remain intact, in contrast to the paradigm in which the activation of GPCRs by nucleotides involves the dissociation of Gα subunits from Gβγ [4,33] c) In this system GDP can initiate the disassembly of ternary complexes, although GDP bound G proteins are generally believed to be "inactive" in cells [33].…”

“…The main points of open discussion have been delineated as follows: 1) How ligand activated GPCRs effect the guanine nucleotide exchange at Gα [36,37]; 2) Whether Gα, Gβγ, and GPCRs remain associated after activation [4,8,38,39]; 3) How the G protein subunits and their effectors are spatially arranged during signaling [6,40].…”

“…The LRG complex on beads is only stable when the pocket is empty and rapidly disassembles when either GDP or GTP are added. Thus the ternary complex formed in live cells survives for the short duration of the dissociative interchange between GDP and GTP [3,4].…”

“…Currently, the consensus model of G protein activation involves the exchange of GDP for GTP catalyzed by ligand-activated GPCR results in the dissociation of the G protein heterotrimer into separate α and βγ subunits which then interact independently with their cognate effectors [3,4]. However, more recent experimental evidence has led to questions about the absolute necessity of including subunit dissociation as an element of activation.…”