G beta-gamma complex

The individual subunits of the G protein complex were first identified in 1980 when the regulatory component of adenylate cyclase was successfully purified, yielding three polypeptides of different molecular weights.[2] Initially, it was thought that G_α, the largest subunit, was the major effector regulatory subunit, and that G_βγ was largely responsible for inactivating the G_α subunit and enhancing membrane binding.[1] However, downstream signalling effects of G_βγ were later discovered when the purified G_βγ complex was found to activate a cardiac muscarinic K+ channel.[3] Shortly after, the G_βγ complex associated with a mating factor receptor-coupled G protein in yeast was found to initiate a pheromone response.[4] Although these hypotheses were initially controversial, G_βγ has since been shown to directly regulate as many different protein targets as the G_α subunit.[1]

Recently, possible roles of the G_βγ complex in retinal rod photoreceptors have been investigated, with some evidence for the maintenance of G_α inactivation. However, these conclusions were drawn from in vitro experiments under unphysiological conditions, and the physiological role of the G_βγ complex in vision is still unclear. Nevertheless, recent in vivo findings demonstrate the necessity of the transducin G_βγ complex in the functioning of rod photoreceptors under low light conditions.[5]

The G_βγ subunit is a dimer composed of two polypeptides, however it acts functionally as a monomer, as the individual subunits do not separate, and have not been found to function independently.[6] The G_β subunit is a member of the β-propeller family of proteins, which typically possess 4-8 antiparallel β-sheets arranged in the shape of a propeller.[7] G_β contains a 7 bladed β-propeller, each blade arranged around a central axis and composed of 4 antiparallel β-sheets.[7] The amino acid sequence contains 7 WD repeat motifs of about 40 amino acids, each highly conserved and possessing the Trp-Asp dipeptide that gives the repeat its name. The G_γ subunit is considerably smaller than G_β, and is unstable on its own, requiring interaction with G_β to fold, explaining the close association of the dimer. In the G_βγ dimer, the G_γ subunit wraps around the outside of G_β, interacting through hydrophobic associations, and exhibits no tertiary interactions with itself. The N terminus helical domains of the two subunits form a coiled coil with one another that typically extends away from the core of the dimer.[7] To date, 5 β-subunit and 11 γ-subunit genes and have been identified in mammals.[6] The G_β genes have very similar sequences, while significantly greater variation is seen in the G_γ genes, indicating that the functional specificity of the G_βγ dimer may be dependent on the type of G_γ subunit involved.[6] Of additional structural interest is the discovery of a so-called “hotspot” present on the surface of the G_βγ dimer; a specific site of the protein that binds to diverse range of peptides and is thought to be a contributing factor in the ability of G_βγ to interact with a wide variety of effectors.[8][9]

The G_βγ complex is an essential element in the GPCR signaling cascade. It has two main states for which it performs different functions. When G_βγ is interacting with G_α it functions as a negative regulator. In the heterotrimer form, the G_βγ dimer increases the affinity of G_α for GDP, which causes the G protein to be in an inactive state.[13] For the G_α subunit to become active, the nucleotide exchange must be induced by the GPCR. Studies have shown that it is the G_βγ dimer that demonstrates specificity for the appropriate receptor and that the G_γ subunit actually enhances the interaction of the G_α subunit with the GPCR.[14][15] The GPCR is activated by an extracellular ligand and subsequently activates the G protein heterotrimer by causing a conformational change in the G_α subunit. This causes the replacement of GDP with GTP as well as the physical dissociation of the G_α and the G_βγ complex.[16]

Once separated, both G_α and G_βγ are free to participate in their own distinct signaling pathways. G_βγ does not go through any conformational changes when it dissociates from G_α and it acts as a signaling molecule as a dimer.[17] The G_βγ dimer has been found to interact with many different effector molecules by protein-protein interactions. Different combinations of the G_β and G_γ subtypes can influence different effectors and work exclusively or synergistically with the G_α subunit.[1]

G_βγ signaling is diverse, inhibiting or activating many downstream events depending on its interaction with different effectors. Researchers have discovered that G_βγ regulates ion channels, such as G protein-gated inward rectifier channels,[3] as well as calcium channels.[18][9] In human PBMC, G_βγ complex has been shown to activate phosphorylation of ERK1/2.[19] Another example of G_βγ signaling is its effect of activating or inhibiting adenylyl cyclase leading to the intracellular increase or decrease of the secondary messenger cyclic AMP.[20] For more examples of G_βγ signaling see table. However, the full extent of G_βγ signaling has not yet been discovered.