TheG beta-gamma complex (G_βγ) is a tightly bound dimeric protein complex, composed of one G_β and one G_γ subunit, and is a component ofheterotrimeric G proteins. Heterotrimeric G proteins, also called guanine nucleotide-binding proteins, consist of three subunits, calledalpha, beta, andgamma subunits, or G_α, G_β, and G_γ. When aG protein-coupled receptor (GPCR) is activated, G_α dissociates from G_βγ, allowing both subunits to perform their respective downstreamsignaling effects. One of the major functions of G_βγ is the inhibition of the G_α subunit.^[1]

The individual subunits of the G protein complex were first identified in 1980 when the regulatory component ofadenylate cyclase was successfully purified, yielding threepolypeptides 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 muscarinicK+ channel.^[3] Shortly after, the G_βγ complex associated with a mating factor receptor-coupled G protein in yeast was found to initiate apheromone 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 retinalrod photoreceptors have been investigated, with some evidence for the maintenance of G_α inactivation. However, these conclusions were drawn fromin vitro experiments under unphysiological conditions, and the physiological role of the G_βγ complex in vision is still unclear. Nevertheless, recentin vivo findings demonstrate the necessity of thetransducin 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 theβ-propeller family of proteins, which typically possess four to eight antiparallel β-sheets arranged in the shape of a propeller.^[7] G_β contains a seven-bladed β-propeller, each blade arranged around a central axis and composed of four antiparallelβ-sheets.^[7] The amino acid sequence contains sevenWD 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 terminushelical domains of the two subunits form acoiled coil with one another that typically extends away from the core of the dimer.^[7] To date, five β-subunit and eleven γ-subunit genes 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]

Synthesis of the subunits occurs in thecytosol. Folding of the β-subunit is thought to be aided by thechaperone CCT (chaperonin containing tailless-complex polypeptide 1), which also prevents aggregation of folded subunits.^[10] A second chaperone, PhLP (phosducin-like protein), binds to the CCT/G_β complex, and is phosphorylated, allowing CCT to dissociate and G_γ to bind. Finally, PhLP is released, exposing the binding site for G_α, allowing for formation of the final trimer at theendoplasmic reticulum, where it is targeted to theplasma membrane.^[11] G_γ subunits are known to beprenylated (covalently modified by the addition of lipid moieties) prior to addition to G_β, which itself has not been found to be modified. This prenylation is thought to be involved in directing the interaction of the subunit both with membrane lipids and other proteins.^[12]

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 forGDP, 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 extracellularligand and subsequently activates the G protein heterotrimer by causing aconformational 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 byprotein-protein interactions. Different combinations of the G_β and G_γ subtypes can influence differenteffectors 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 regulatesion channels, such asG protein-gated inward rectifier channels,^[3] as well ascalcium channels.^[18][9] In humanPBMC, G_βγ complex has been shown to activate phosphorylation ofERK1/2.^[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 messengercyclic AMP.^[20] For more examples of G_βγ signaling see table. However, the full extent of G_βγ signaling has not yet been discovered.

The G_βγ subunit plays a variety of roles in cell signalling processes and as such researchers are now examining its potential as a therapeutic drug target for the treatment of many medical conditions. However, it is recognized that there are a number of considerations to keep in mind when designing a drug which targets the G_βγ subunit:

1. The G_βγ subunit is essential for the formation of heterotrimeric G protein through its association with the G_α subunit allowing the G proteins coupling to the GPCR. Therefore, any agent inhibiting the G_βγ subunits signalling effects must not interfere with the heterotrimeric G protein formation or G_α subunit signalling.
2. G_βγ expression is universal throughout almost all the cells of the body so any agent acting to inhibit this subunit could elicit numerous side effects.
3. Small molecule inhibitors that target the coupling of G_βγ to specific effectors and do not interfere with normal G protein cycling/ heterotrimeric formation, have the potential to work as therapeutic agents in treating some specific diseases.^[17]

Research has been conducted on how altering the actions of G_βγ subunits could be beneficial for the treatment of certain medical conditions. G_βγ signalling has been examined for its role in a variety of conditions includingheart failure,inflammation andleukemia.^[17][21]

Heart failure can be characterized by a loss ofβ adrenergic receptor (βAR) signalling in heart cells.^[22] When the βAR is stimulated bycatecholamines such asadrenaline andnoradrenaline, there is normally an increase in the contractility of the heart. However, in heart failure there are sustained and elevated levels of catecholamines which result in chronicdesensitization of the βAR receptor. This leads to a decrease in the strength of heart contractions. Some research suggests that this chronic desensitization is due to the over activation of a kinase,G protein-coupled receptor kinase 2 (GRK2), which phosphorylates and deactivates certain G protein coupled receptors .^[23] When the G protein coupled receptor is activated, the G_βγ subunit recruits GRK2 which then phosphorylates and desensitizes GPCRs like the βAR.^[24] Preventing the interaction of the βγ subunit with GRK2 has therefore been studied as a potential target for increasing heart contractile function. The developed molecule GRK2ct is a protein inhibitor which inhibits the signalling properties of G_βγ subunit but does not interfere with alpha subunit signalling.^[25] The over expression of GRK2ct has been shown to significantly rescue cardiac function inmurine models of heart failure by blocking G_βγ subunit signalling.^[26] In another study, biopsies were taken from patients with heart failure andvirally induced overexpression of GRK2ct in the heartmyocytes. Other tests showed an improvement in cardiac cell contractile function by inhibiting G_βγ.^[27]

When particular GPCRs are activated by their specificchemokines G_βγ directly activatesPI3Kγ which is involved in the recruitment ofneutrophils that contribute to inflammation.^{[28][29][30][31]} It has been discovered that the inhibition of PI3Kγ significantly reduces inflammation.^[28][29] PI3Kγ is the intended target molecule in the prevention of inflammation as it is the common signalling effector of many different chemokine and receptor types involved in promoting inflammation.^[30][31] Although PI3Kγ is the intended target there are otherisoforms ofPI3 which perform different functions from PI3Kγ. Since PI3Kγ is specifically regulated by G_βγ, while other isoforms of PI3 are largely regulated by other molecules, inhibiting Gβγ signalling would provide the desired specificity of a therapeutic agent designed to treat inflammation.^[17]

The G_βγ subunit has been shown to activate aRho guanine nucleotide exchange factor (RhoGef) genePLEKHG2 which isupregulated in a number of leukemia cell lines and mouse models of leukemia.^[32]Lymphocytechemotaxis as a result ofRac andCDC42 activation as well asactinpolymerization is believed to be regulated by the G_βγ activated RhoGef. Therefore, a drug inhibiting the G_βγ could play a role in the treatment of leukemia.^[21]

• G proteins
• Protein complexes

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