Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

G Protein Beta/Gamma

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_75

Synonyms

Isoforms

Five different isoforms of Gbeta have been identified, numbered 1 to 5. Ggamma isoforms are numbered from 1 to 5 and 7 to 13.

G protein beta5 can also be known as Flailer, Flail, Flr, Hug.

G protein gamma2 is also known as G protein gamma6.

Historical Background

G protein β and γ subunits were first discovered as components of G proteins over 30 years ago. Since then, their role has evolved significantly from simple inhibitors of  G protein α subunits to independent signaling regulators modulating a number of different cellular effectors. Although several isoforms of Gα were cloned in the early 1980s, it was not until 1986 that the transducin Gβ subunit was cloned (Fong et al. 1986). The following year, a second Gβ subunit was identified and the count rapidly increased to five different genes. Gβ1-4 shared 82–92% identity, while Gβ5 shared only 51–53% identity with the other four isoforms. As was the case for Gα and Gβ, the first Gγ subunit to be cloned was also from transducin (Hurley et al. 1984). The Gγ subunits are more structurally diverse than the Gβ subunits; 12 nonallelic mammalian Gγ genes encode proteins of between 68 and 75 amino acids that share between 27% and 76% sequence homology. If divided into subfamilies, the sequence similarities among family members are much greater. For example, Gγ1, Gγ11, and Gγ13 share 62–73% homology. Gγ subunits undergo several posttranslational modifications including isoprenylation of an invariant cysteine residue in a conserved CAAX motif at the carboxyl end of the protein which have been demonstrated to be important for membrane localization of Gβγ. Most Gγ subunits have a leucine at the carboxyl terminus which directs addition of a geranylgeranyl group, while some (Gγ1, Gγ8, Gγ11, and Gγ13) have a serine which permits addition of a farnesyl group. Gγ subunits form tight (essentially non-dissociable) complexes with Gβ, and confer structural diversity and functional diversity to the Gβγ signaling complex. Although Gβγ is made up of two polypeptides, Gβ and Gγ, it essentially exists as a single protein as they do not dissociate in the absence of denaturing agents. The high resolution structure of the Gβγ subunit was first elucidated in the context of the G protein heterotrimer (Lambright et al. 1996). Subsequently, the structure of the Gβγ dimer alone was solved (Sondek et al. 1996). The Gβ subunit is folded into four stranded β-sheets forming each of the seven blades of the prototypical circular β-propeller. The circular structure is held closed by a molecular “Velcro snap” in the seventh blade of the propeller. The first 57–70 amino acids N-terminal to the β-propeller form an α-helical domain, which is tightly associated with the Gγ subunit in a coiled-coil interaction.

Five different Gβ subunits and 12 different Gβγ subunits genes have been identified in the human and mouse genomes. The different subunits can pair to form unique Gβxγx combinations, which contribute to the functional diversity of Gβγ signaling. Interpretation of phenotypes resulting from knockout of individual Gβγ subunits has failed to provide a clear picture of the role of each subunit, as Gβγ subunits participate in multiple, integrated functional interactions with receptors, Gα subunits, and effectors. Surprisingly, knockout of the Gβ1 subunit, despite its homology with Gβ2-4, was embryonic lethal (Okae and Iwakura 2010). This suggests that the different Gβ subunits are developmentally regulated. This has been demonstrated directly for Gβ3 subunits in cardiomyocytes (Rybin and Steinberg 2008). Nevertheless, there is evidence suggesting that specific Gβγ subtypes interact with particular G protein-coupled receptors (GPCR). Genetic deletion of specific Gγ subunits in mice results in specific phenotypes. For example, deletion of Gγ7 resulted in distinct behavioral changes associated with loss of cAMP production in the striatum, while deletion of Gγ3 induced changes in metabolism resulting in resistance to a high fat diet (Schwindinger et al. 2003).

If all Gβ subunits interact and randomly form dimers with all Gγ subunits, there would be 60 possible combinations in total. Most can form pairs in vitro but some exceptions have been reported. For example, Gβ1 can combine with all known Gγ subunits, while Gβ2 was shown to be more selective, associating with Gγ2, but not Gγ1. The region of Gγ defining the specificity of interaction with Gβ subunits has been localized to a 14-amino acid segment located toward the middle of the molecule (Spring and Neer 1994). Gβ5 is clearly an outlier with respect to sequence and its capacity to interact with Gγ. While Gβ5 can interact with some Gγ subunits, it appears to be weakly bound and the complex can be separated under non-denaturing conditions. Biochemical studies demonstrated that RGS7 formed stable complexes with Gβ5, but not other Gβ subunits (Cabrera et al. 1998) and was co-purified as a tight complex, while no Gγ subunit was found to co-purify or form stable complexes with Gβ5 (Witherow et al. 2000). Another study examining Gβ5 complex formation with different potential partners showed that Gβ5 slightly prefers Gγ2 relative to RGS7, suggesting that in native tissues, Gγ2 could potentially assemble with Gβ5 unless there is a tight regulation of this interaction by molecular chaperones (Yost et al. 2007).

While functional Gα subunits can be synthesized in almost any expression system, Gβγ synthesis seems more tightly regulated. This is not simply owing to differential posttranslational modification as both Gα and Gγ subunits are modified by the addition of lipid moieties that facilitate their association with lipid bilayers. For example, Gβγ can be synthesized in vitro in rabbit reticulocyte lysates. However, either cotranslationally or by subsequent attempts at assembly in vitro, formation of functional Gβγ dimers is inefficient; only 30–50% of the synthesized Gβ and Gγ subunits can form functional Gβγ dimers. Interestingly, Gβ subunits can be synthesized separately from Gγ subunits in rabbit reticulocytes and wheat germ extract, but these will not interact efficiently with Gγ subunits. By contrast, Gγ subunits can be synthesized in rabbit reticulocyte lysates, wheat germ extracts, and bacteria, and will efficiently associate with Gβ subunits. This specificity suggests that molecular chaperones are necessary for the proper folding of Gβ and subsequent assembly into a Gβγ dimer. Recent studies have indicated that there are preferential associations of such chaperone candidates for different Gβγ subunits in living cells. Members of the phosducin family were originally proposed to act as inhibitors of G protein signaling via sequestration of the Gβγ subunits from Gα and effector molecules. Phosducin-like proteins (PhLP 1–3) have been shown to serve as co-chaperones with the cytosolic chaperonin complex (CCT) to assist in folding a variety of nascent proteins (Martin-Benito et al. 2004; Lukov et al. 2006). CCT is an essential chaperone required for protein folding in the cytosol of eukaryotic cells. Among the known substrates of CCT are Gα and multiple proteins with β-propeller WD40 structures similar to Gβ. PhLP acts as a co-chaperone by binding above the CCT cavity and occluding the cavity to stabilize folding processes until native protein formation occurs. PhLP1 may act as a co-chaperone for the folding of the Gβ subunit until Gβγ reaches its native stable state. This idea is consistent with observations that when PhLP1 is deleted in Dictyostelium, Gβ does not colocalize with Gγ at the plasma membrane but is expressed in the cytosol, as if the Gγ interaction was inhibited. To facilitate Gβγ dimer formation, PhLP1 must be phosphorylated on serine residues by  casein kinase 2 (CK2). A mutant of PhLP1 that cannot be phosphorylated (S18–20A) inhibits both Gβ release from CCT and subsequent Gβγ assembly. The mechanism for Gβ release from CCT may involve steric repulsion, thereby triggering release of a PhLP1-Gβ complex intermediate. Here, Gβγ subunits are not yet in their native form because the intermediate complex of PhLP1-Gβ does not contain Gγ subunits (Dupre et al. 2009; Lukov et al. 2006; Willardson and Howlett 2007).

Interestingly, Gγ was not found to interact with CCT either directly or in a complex with Gβ. A separate chaperone has also been identified for Gγ subunits. Dopamine receptor interacting protein 78 (DRiP78) is an ER membrane–bound HSP40 co-chaperone that regulates receptor transport to the plasma membrane of GPCRs such as β2-adrenergic (β2AR), dopamine D1, M2 muscarinic cholinergic, and angiotensin II AT1 receptors (Bermak et al. 2001; Leclerc et al. 2002; Dupre et al. 2007). Gγ subunits and DRiP78 initially colocalize in the ER, presumably facing the cytosolic compartment where they can interact with Gβ. It was suggested that DRiP78 maintains the stability of nascent Gγ in the absence of its heterotrimeric partners. Furthermore, DRiP78 interacts directly with PhLP1, suggesting that PhLP-Gβ complex might interact with DRiP78-Gγ complex, thus participating in the assembly of the native Gβγ dimer. DRiP78 acts as a co-chaperone for Gβγ assembly, protecting Gγ from degradation until both subunits can be assembled into their native form (Dupre et al. 2009).

Role in G Protein Coupled Receptor Assembly, Organization, and Signaling

Receptors, G proteins, effectors, as well as several scaffolding/chaperone proteins are observed as multimeric complexes at the plasma membrane. Some studies have suggested that several of these signaling partners can form complexes before receptor activation by agonist, that is, they are pre-associated complexes. A rather confusing picture regarding the trafficking of individual components of GPCR signaling complexes has appeared in recent years. While it is clear that receptor oligomers themselves are assembled in the endoplasmic reticulum, the site of the assembly of the rest of the core signaling components was still unclear. Constitutive trafficking of some GPCR-regulated effectors, such as adenylyl cyclase isoforms or various ion channels, demonstrates that components of these signaling pathways can make their way to the membrane independently of the receptor or G protein. However, there is now significant evidence that like GPCR oligomers, these complexes are also formed early in their maturation steps. A number of studies have also demonstrated that receptors can directly interact with Gβγ subunits as well as Gα subunits (Wu et al. 1998, 2000; Mahon et al. 2006) and that many of these proteins interact initially in the endoplasmic reticulum (ER), including receptor dimers, receptor and Gβγ subunits, and effectors such as Kir3 channels and  adenylyl cyclase with nascent Gβγ (Dupre et al. 2006; Rebois et al. 2006). If these complexes are preformed during protein biosynthesis and maturation, they would need to be trafficked inside the cell as a complex and not necessarily as individual proteins (Fig. 1). It is clear that both GPCRs and their effector molecules interact with G protein subunits before targeting to the plasma membrane. It has been suggested that Gβγ subunits might play an organizing role for assembly of GPCR-based signaling complexes as they interact with all of the relevant components, receptor, Gα, and effectors before any of them reach their destination. A potential mechanism may rely on early interactions with G protein subunits which may regulate assembly of receptor signaling complexes in the ER as when Gβγ function is inhibited by using a membrane-localized GRK2ct construct, Kir3.1/Gβγ complex formation in the ER can be blocked. Although still in its infancy, it seems that current research points toward an important role of Gβγ in signaling complex organizations.
G Protein Beta/Gamma, Fig. 1

Schematic representation of a cell and assembly sites of G protein subunits, receptors, and effectors

G Protein βγ Regulation of Effectors

Early reconstitution studies with receptors and purified G proteins indicate that Gβγ is required for GPCR-induced nucleotide exchange. While some studies suggested Gβγ was necessary for the targeting of Gα subunits to the receptor, others have suggested that Gβγ might not only promote coupling, but also organize the structure of the Gα subunit so it is a substrate for GPCRs. Gβγ subunits can also regulate a wide range of effectors. Although various Gβγ binding motifs within effectors have been identified, no single consensus sequence or structure has been identified. However, energetic hot spots have been identified on the surface of Gβγ which allow several types of chemical interactions (ionic, hydrophobic), with multiple structural and chemical motifs at a single binding site (DeLano 2002; Fairbrother et al. 1998; Ma et al. 2001; Scott et al. 2001). Two general mechanisms for Gβγ-dependent regulation of effectors were proposed, according to the localization of the effector. In the case of cytosolic proteins like PLCβ2 or GRK2, whose substrates are membrane-bound, a potential mechanism for activation is via membrane-bound Gβγ recruitment to the effector. Membrane-embedded targets like Kir3 channels and adenylyl cyclase would be regulated via conformational changes. Some examples of different Gβγ effectors are given in Table 1, and a brief overview of the mechanisms used to regulate some effectors is presented here.
G Protein Beta/Gamma, Table 1

Some Gβγ targets (Clapham and Neer 1997)

Effector

Regulation

Direct

N type, P/Q type Ca2+ channels

+

+

Inwardly rectifying K+ channel GIRK/GIRK2, GIRK1/GIRK4

+

+

Phospholipase A2

+

 

PLCβ1, PLCβ2, PLCβ3

+

+

Adenylyl cyclase type II, type IV, type VII (activation)

+

+

Adenylyl cyclase type I, type III, type V, type VI (inhibition)

+

+

G protein coupled receptor kinases (GRK2 and GRK3)

+

+

Phosphoinositide 3 kinase γ

+

+

Raf-1

+

 

SNAP-25

+

+

Bruton tyrosine kinase

+

 

Dynamin

+

 

RGS3, RGS4

+

 

P-Rex1 Rac GEF

+

+

Gβγ is known to regulate several ion channels, such as Kir3 (inward rectifier G protein-gated K+ channel) and voltage-gated calcium channels. The model of activation of membrane-bound channels such as Kir3 suggests that Gβγ binding to an intracellular cytosolic domain of the channel strengthens interactions between PIP2 and the channel, which alters the structure at the mouth of the conductance pore to increase channel activity. PLCβ activation by Gβγ relies on the alteration of its enzymatic activity either through conformational alteration of the active isoforms or modulation of the orientation of PLC with respect to membrane surface (Romoser et al. 1996; Runnels et al. 1996). Evidence for the alteration of enzymatic activity comes from studies showing that fragments of PLCβ2 could compete for the PLCβ2 activation by Gβγ in transfected cells. Two overlapping fragments from the catalytic Y domain of PLC blocked activation by Gβγ or a Gαi coupled C5A receptor, but not Gαq coupled α1-adrenergic receptor (Kuang et al. 1996). A triple substitution (E574, L575, K576) in the PLCβ2 catalytic domain disrupted direct binding of Gβγ to PLCβ2, strongly suggesting that the region involved in the activation of PLCβ2 is also mediating the interaction (Bonacci et al. 2005; Sankaran et al. 1998). Supporting the notion that a pleckstrin homology (PH) domain is involved is the observation that the isolated PH domain from PLCβ2 interacts with Gβγ on membrane surfaces and splicing of the PH domain to PLCd confers the ability for PLCd to be activated by Gβγ (Wang et al. 2000). Further biochemical and structural analysis will be required to determine the exact mechanism involved in the process.

Gβγ will not only regulate classic GPCR signaling effectors, but also seems to be involved in vesicular traffic. Heterotrimeric G proteins are associated with intracellular membrane compartments. For example, it was shown that purified Gβγ subunits inhibited the export of a marker protein from the endoplasmic reticulum (Schwaninger et al. 1992). Although the exact mechanisms are still unclear, both Gαs and Gβγ interact with the small GTPase ARF (Colombo et al. 1995), important for vesicular trafficking. Also, the association of ARF and β-COP with Golgi membranes is sensitive to a number of reagents that modulate heterotrimeric G protein function (Donaldson et al. 1991; Ktistakis et al. 1992). Interestingly, ARF might be an exception in the small GTPases family, as Rab, Ras, Rho, and their relatives did not display binding capacity to Gβγ subunits. The Ras exchange factor  CDC25Mm or p140Ras-GRF could become constitutively activated following co-expression with Gβ1γ2 or Gβ1γ5, classifying it as a Gβγ-sensitive pathway.

Receptor-Independent Signaling by G Protein βγ

The classical view holds that GPCR signaling was mediated solely via activation of G proteins and their downstream effectors. However, an emerging area of research is non-receptor and nucleotide exchange-independent mechanisms for G protein activation (Luttrell 2005). Some of the mechanisms used to activate Gβγ involve binding to Gα, leading to the release of free Gβγ. Other proteins have been found to directly activate Gβγ via a direct interaction; however, the mechanisms remain poorly understood. Below is a sampling of these events.

Several activators of G protein signaling (AGS) have been identified to date. Group I AGS proteins are guanine nucleotide exchange factors that promote receptor-independent G protein activation by facilitating GDP dissociation from, and thus GTP binding to, Gα subunits. Group II AGS proteins (also called GPR or GoLoco proteins), in contrast, inhibit GDP dissociation, but may promote Gβγ signaling by altering the association between Gα and Gβγ. Group III AGS proteins differ from the others in that they do not appear to bind appreciably to Gα subunits but rather they produce their effects by binding directly to Gβγ. This interaction could promote dissociation of the heterotrimer subunits or simply compete for interaction with Gα. AGS2, a light chain component of the dynein motor in the cytoplasm may also be a direct Gβγ effector important for the modulation of neurite outgrowth and other processes required dynamic modulation of the cytoskeleton (Sachdev et al. 2007). Another study indicated that AGS9, a Group III AGS protein, modulated signaling events via interactions with an intact G protein heterotrimer, and may in fact form a signaling complex with the G protein heterotrimer and one of the classic Gβγ effectors, PLCβ (Yuan et al. 2007). However the exact function of the Group III AGS proteins remains unclear. Gβ1 can be phosphorylated on histidine 266 by histidine kinase and this high energy phosphate can be transferred to Gα-GDP, yielding Gα-GTP, by nucleoside diphosphate kinase B (NDPK B) (Wieland 2007). This may represent a mechanism for heterotrimeric G protein activation which does require a GPCR per se. In rat cardiomyocytes, Gβ1 H266L, a mutant which cannot be phosphorylated by histidine kinase showed reduced cAMP stimulation and reduced levels of cardiac contractility and decreased phosphorylation of phospholamban on serine 16 following receptor stimulation by agonist (Hippe et al. 2007).

G Protein βγ as a Target for Therapeutic Development

The diversity of physiological Gβγ functions in the cell suggests that their specific manipulation might be of significant therapeutic interest. Although the blockade of Gβγ in cells is a highly promising target, selective manipulation would be required. Indeed, the type of compound that would be preferred would be a small molecule capable of binding to Gβγ and affecting particular downstream signaling events, without affecting other vital functions of the heterotrimeric G protein (Gαβγ) and GPCR activation. Interestingly, some molecules have been found to act in such way. For example, the carboxy terminus of GRK2 (GRK2ct) (Koch et al. 1995) was used in cardiac cells to demonstrate the therapeutic potential of targeting Gβγ in cardiac function and failure. During heart failure, a loss of β-adrenergic receptor (βAR)-dependent expression is observed, where it has been shown that receptor desensitization following GRK2 phosphorylation of the receptor is occurs. GRK2 is controlled by Gβγ which, following GPCR activation, recruits GRK2 to the receptor leading to receptor phosphorylation. GRK2ct blocks this recruitment and permits continuation of receptor function, as demonstrated in transgenic cardiac overexpression of GRK2ct in mice where cardiac performances were improved following β-adrenergic receptor stimulation. Another study demonstrated in cardiomyocytes isolated from human biopsies that expression of GRK2ct could significantly improve contractile function (Williams et al. 2004).

Peptides with the capacity to bind directly to Gβγ as observed for the SIRK/SIGK peptides. Although these peptides were shown to block Gβγ-dependent PLCβ2 and PI3Kγ activation in vitro, while they had no effect on the inhibition of  adenylate cyclase, demonstrating selectivity for inhibition of some Gβγ targets. Cell-permeable versions of the peptides predicted to inhibit G protein signaling demonstrated rapid, efficient, and potent activation of the ERK/MAPK pathway, while a Gβ mutant (W332A), unable to bind the peptide showed significantly inhibited SIRK-dependent ERK activation (Malik et al. 2005).

These molecules could represent potentially specific Gβγ targets in inflammation, as well as drug addiction. Although one major therapeutic target, chemokines and their receptors physiology is extremely complex, due to their natural tendency for redundancy and the multitude of chemokines and receptors that can be expressed in a single cell. These considerations make it difficult to convincingly identify the factors responsible for inflammatory diseases such as arthritis. Gβγ regulates some downstream effectors such as PI3Kγ, which was shown to be involved in the regulation of neutrophil migration in response to chemoattractants and inhibition of inflammation. In this system, inhibition of PI3Kγ would bypass the inhibited interactions between Gβγ and targets that are critical for chemoattractant-dependent directed migration or reactive oxygen species production by neutrophils or other monocytes (Lehmann et al. 2008). For example, M119 blocked membrane translocation of  P-Rex, a PIP3- and Gβγ-regulated Rac2 exchange factor, in neutrophils. This action could result from direct blockade of P-Rex binding to Gβγ in addition to blocking PIP3 production by  PI 3-kinase (Lehmann et al. 2008; Zhao et al. 2007). In vivo validation of small molecules targeting Gβγ has been shown in studies of opioid-dependent nociception (Mathews et al. 2008). M119, when injected intracerebroventricularly in mice, could cause tenfold and sevenfold increases in the potencies of morphine and the μ-opioid receptor peptide DAMGO, respectively, while having little or no effect on the γ- or δ-opioid receptor dependent analgesic pathways. M119 also inhibited μ-opioid receptor dependent activation of PLC, and systemic administration of M119 resulted in a fourfold shift increase in potency of systemically administered morphine. A recent study showed that inhibition of Gβγ signaling with small molecules based on these peptides (M119) was protective in heart failure models (Casey et al. 2010). These results suggest that small organic compounds that specifically regulate Gβγ signaling could have important therapeutic applications in several diseases.

Summary

Gβγ are important modulators of cellular function, highly implicated in G protein signaling, and possibly the scaffolding of receptors with their signaling partners. Despite years of investigation, the selectivity of assembly of the different subunits and the specific function of all these pairs is still poorly understood. It is likely that in the near future, new properties, mechanisms of action and functions will emerge which might provide us with a better understanding of the role of this key component in signal transduction. Given the large potential for therapeutic strategies targeting Gβγ, understanding how these proteins work in physiological systems will likely provide answers as to how we can manipulate them to develop novel therapeutic approaches to several diseases.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Faculty of MedicineDalhousie UniversityHalifaxCanada
  2. 2.Department of Pharmacology and TherapeuticsMcGill UniversityMontréalCanada